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Enzalutamide‐Resistant STEAP4+ MyoCAF Secrete Phosphatidylcholine to Foster Progression by Activating Stemness in Hormone‐Sensitive Prostate Cancer

Expanding enzalutamide (ENZ) use in hormone‐sensitive prostate cancer (HSPC) faces resistance. Single‐cell profiling identifies therapy‐resistant STEAP4+ myofibroblastic cancer‐associated fibroblast (SETAP4+ myoCAF). These myoCAFs drive resistance via TFE3‐mediated autophagy and PCYT1A‐led phosphatidylcholine overproduction, creating a phospholipid‐rich niche that activates tumor HSP90/HIF1A, promoting stemness and revealing actionable therapeutic targets for HSPC. Abstract Despite the expanding clinical application of second‐generation anti‐androgens like enzalutamide (ENZ) in hormone‐sensitive prostate cancer (HSPC), therapeutic resistance culminating in castration‐resistant prostate cancer (CRPC) persists as an unresolved clinical crisis. Through comprehensive single‐cell transcriptomic profiling of ENZ‐naïve and ENZ‐treated tumors, an expansion of ENZ‐resistant myofibroblastic cancer‐associated fibroblast (designated STEAP4+ myoCAF) is identified that correlates with adverse clinical outcomes. Strikingly, STEAP4+ myoCAF demonstrated intrinsic ENZ resistance through a mechanistically novel pathway involving transcription factor binding to IGHM enhancer 3 (TFE3)‐mediated autophagy activation. Integrated lipidomic and functional analyses revealed that TFE3 activation drives phosphatidylcholine overproduction via direct upregulation of phosphate cytidylyltransferase 1A (PCYT1A), establishing a tumor‐promoting feedforward loop. The resultant phospholipid‐rich microenvironment activates an HSP90/HIF1A signaling axis in malignant epithelial cells, fueling cancer stemness and therapeutic escape. These findings position the STEAP4+ myoCAF‐TFE3/tumor‐HIF1A axis as a master regulator of anti‐androgen resistance, offering clinically actionable targets to extend treatment efficacy in advanced prostate cancer. Expanding enzalutamide (ENZ) use in hormone-sensitive prostate cancer (HSPC) faces resistance. Single-cell profiling identifies therapy-resistant STEAP4 + myofibroblastic cancer-associated fibroblast (SETAP4 + myoCAF). These myoCAFs drive resistance via TFE3-mediated autophagy and PCYT1A-led phosphatidylcholine overproduction, creating a phospholipid-rich niche that activates tumor HSP90/HIF1A, promoting stemness and revealing actionable therapeutic targets for HSPC. Abstract Despite the expanding clinical application of second-generation anti-androgens like enzalutamide (ENZ) in hormone-sensitive prostate cancer (HSPC), therapeutic resistance culminating in castration-resistant prostate cancer (CRPC) persists as an unresolved clinical crisis. Through comprehensive single-cell transcriptomic profiling of ENZ-naïve and ENZ-treated tumors, an expansion of ENZ-resistant myofibroblastic cancer-associated fibroblast (designated STEAP4 + myoCAF) is identified that correlates with adverse clinical outcomes. Strikingly, STEAP4 + myoCAF demonstrated intrinsic ENZ resistance through a mechanistically novel pathway involving transcription factor binding to IGHM enhancer 3 (TFE3)-mediated autophagy activation. Integrated lipidomic and functional analyses revealed that TFE3 activation drives phosphatidylcholine overproduction via direct upregulation of phosphate cytidylyltransferase 1A (PCYT1A), establishing a tumor-promoting feedforward loop. The resultant phospholipid-rich microenvironment activates an HSP90/HIF1A signaling axis in malignant epithelial cells, fueling cancer stemness and therapeutic escape. These findings position the STEAP4 + myoCAF-TFE3/tumor-HIF1A axis as a master regulator of anti-androgen resistance, offering clinically actionable targets to extend treatment efficacy in advanced prostate cancer. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Stage‐Resolved Phosphoproteomic Landscape of Mouse Spermiogenesis Reveals Key Kinase Signaling in Sperm Morphogenesis

The quantitative proteomic and phosphoproteomic profiling reveals dynamic phosphorylation regulation of sperm morphogenesis. Kinase‐substrate phosphorylation network and phosphorylation module analysis, followed by in vivo knockdown and knockout analysis, identify TTBK2 and CSNK1G1 as key regulators of morphogenesis, including head, flagellar, and acrosomal development. This study provides insights into the temporal control of phosphorylation signaling during spermiogenesis, offering a valuable resource. Abstract Spermiogenesis is the committed step of sperm production, during which spermatid cells undergo dramatic morphological transformations and transcriptional silencing. Post‐translational modifications (PTMs), including phosphorylation, provide a level of protein function flexibility and play important roles in spermiogenesis. Dynamic protein phosphorylation profiles of spermatids are characterized across four different developing steps, and identified phosphorylation regulation of key proteins in spermiogenesis. Expression module and kinase‐substrate phosphorylation network analysis revealed significant kinase activities of CSNK1G1 and TTBK2. CSNK1G1 is localized in the acrosome and is indispensable for acrosome biogenesis. Ttbk2 male germ cell conditional knockout mice are infertile with flagella development and head shaping defects. TTBK2 is essential for both the phosphorylation and stabilization of IFT88, an intraflagellar transport (IFT) protein with which TTBK2 colocalizes and interacts. Ciliogenesis defects in Ttbk2 knockout cells can be rescued by overexpression of TTBK2 or IFT88 but not kinase‐dead TTBK2. Collectively, the systematic profiling of the spermiogenesis phosphoproteome revealed the dynamic nature and important functions of kinase phosphorylation in spermiogenesis and male fertility. The quantitative proteomic and phosphoproteomic profiling reveals dynamic phosphorylation regulation of sperm morphogenesis. Kinase-substrate phosphorylation network and phosphorylation module analysis, followed by in vivo knockdown and knockout analysis, identify TTBK2 and CSNK1G1 as key regulators of morphogenesis, including head, flagellar, and acrosomal development. This study provides insights into the temporal control of phosphorylation signaling during spermiogenesis, offering a valuable resource. Abstract Spermiogenesis is the committed step of sperm production, during which spermatid cells undergo dramatic morphological transformations and transcriptional silencing. Post-translational modifications (PTMs), including phosphorylation, provide a level of protein function flexibility and play important roles in spermiogenesis. Dynamic protein phosphorylation profiles of spermatids are characterized across four different developing steps, and identified phosphorylation regulation of key proteins in spermiogenesis. Expression module and kinase-substrate phosphorylation network analysis revealed significant kinase activities of CSNK1G1 and TTBK2. CSNK1G1 is localized in the acrosome and is indispensable for acrosome biogenesis. Ttbk2 male germ cell conditional knockout mice are infertile with flagella development and head shaping defects. TTBK2 is essential for both the phosphorylation and stabilization of IFT88, an intraflagellar transport (IFT) protein with which TTBK2 colocalizes and interacts. Ciliogenesis defects in Ttbk2 knockout cells can be rescued by overexpression of TTBK2 or IFT88 but not kinase-dead TTBK2. Collectively, the systematic profiling of the spermiogenesis phosphoproteome revealed the dynamic nature and important functions of kinase phosphorylation in spermiogenesis and male fertility. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Allele‐Specific Regulation of PAXIP1‐AS1 by SMC3/CEBPB at rs112651172 in Psychiatric Disorders Drives Synaptic and Behavioral Dysfunctions in Mice

This study identifies a functional noncoding variant, rs112651172 (C/G), that drives allele‐specific expression of PAXIP1‐AS1 in monozygotic twin pairs discordant for schizophrenia and bipolar disorder. The risk G allele enhances CEBPB binding, leading to lncRNA upregulation, CNTNAP3 derepression, and synaptic and behavioral deficits in mice. These findings highlight ASE‐mediated lncRNA dysregulation as a novel mechanism and therapeutic targets in psychiatric pathogenesis. Abstract Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex genetic and environmental underpinnings. Allele‐specific expression (ASE) has emerged as a critical mechanism linking noncoding genetic variants to disease risk through epigenetic and environmental modulation. Here, whole‐genome and transcriptome analyses of monozygotic twin pairs discordant for BPD or SCZ are performed, identifying that noncoding genetic variants drive differential ASE patterns of long noncoding RNAs (lncRNAs) in affected individuals compared to their unaffected co‐twins. The rs112651172 (C/G) is identified as a functional ASE variant regulating PAXIP1‐AS1 expression via allele‐specific transcription factor binding: SMC3 binds the C allele, while CEBPB binds the G allele, resulting in G allele‐specific upregulation in patients. Eevated PAXIP1‐AS1 expression is consistently observed in SCZ and BPD postmortem brain tissues from PsychENCODE or LIBD datasets. In mice, G allele overexpression in the prefrontal cortex induces anxiety‐ and depression‐like behaviors, social deficits, memory impairments, sensorimotor gating abnormalities, and reduced neuronal excitability. Mechanistically, PAXIP1‐AS1 upregualtes CNTNAP3 by sequestering the transcriptional repressor ZGPAT. Knockdown of CNTNAP3 reversed the observed phenotypes. These findings establish rs112651172 as a regulatory variant linking noncoding genetic risk to psychiatric phenotypeshrough ASE‐driven lncRNA dysregulation, suggesting new therapeutic targets in SCZ and BPD. This study identifies a functional noncoding variant, rs112651172 (C/G), that drives allele-specific expression of PAXIP1-AS1 in monozygotic twin pairs discordant for schizophrenia and bipolar disorder. The risk G allele enhances CEBPB binding, leading to lncRNA upregulation, CNTNAP3 derepression, and synaptic and behavioral deficits in mice. These findings highlight ASE-mediated lncRNA dysregulation as a novel mechanism and therapeutic targets in psychiatric pathogenesis. Abstract Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex genetic and environmental underpinnings. Allele-specific expression (ASE) has emerged as a critical mechanism linking noncoding genetic variants to disease risk through epigenetic and environmental modulation. Here, whole-genome and transcriptome analyses of monozygotic twin pairs discordant for BPD or SCZ are performed, identifying that noncoding genetic variants drive differential ASE patterns of long noncoding RNAs (lncRNAs) in affected individuals compared to their unaffected co-twins. The rs112651172 (C/G) is identified as a functional ASE variant regulating PAXIP1-AS1 expression via allele-specific transcription factor binding: SMC3 binds the C allele, while CEBPB binds the G allele, resulting in G allele-specific upregulation in patients. Eevated PAXIP1-AS1 expression is consistently observed in SCZ and BPD postmortem brain tissues from PsychENCODE or LIBD datasets. In mice, G allele overexpression in the prefrontal cortex induces anxiety- and depression-like behaviors, social deficits, memory impairments, sensorimotor gating abnormalities, and reduced neuronal excitability. Mechanistically, PAXIP1-AS1 upregualtes CNTNAP3 by sequestering the transcriptional repressor ZGPAT. Knockdown of CNTNAP3 reversed the observed phenotypes. These findings establish rs112651172 as a regulatory variant linking noncoding genetic risk to psychiatric phenotypeshrough ASE-driven lncRNA dysregulation, suggesting new therapeutic targets in SCZ and BPD. Advanced Science, Volume 12, Issue 44, November 27, 2025.

The Role of Operating Temperature on Pore‐Scale Gas Transport in Polymer Electrolyte Membrane Electrolyzers

This study clarifies the critical relationship between operating temperature and two‐phase flow behavior in polymer electrolyte membrane (PEM) electrolyzers by investigating pore‐scale gas bubble transport in the anode porous transport layer. Higher temperatures (80 °C vs 40 °C) result in a lower total bubble volume fraction and smaller bubble diameters, driven by enhanced water transport and increased bubble detachment rates. Abstract In this study, the effects of operating temperature on pore‐scale gas bubble transport in a carbon‐based anode porous transport layer (PTL) of a polymer electrolyte membrane (PEM) electrolyzer is revealed using operando X‐ray computed tomography (CT). Higher temperature operation (80 °C compared to 40 °C) led to a lower total gas bubble volume fraction in the PTL (0.25 to 0.17; 32% lower), which is attributed to improved water transport and gas removal. Higher temperatures led to fewer bubbles in the PTL (13% less at 80 °C compared to 40 °C) as well as a greater occurrence of smaller bubbles (35% increase in skewness of the bubble size distribution), and this behavior is attributed to faster rates of nucleation and bubble detachment from the electrode. The formation of gas slugs is also observed in the anode channels at 60 °C and 80 °C, which is attributed to the faster detachment and coalescence of bubbles from the PTL/flow field interface. This study clarifies the critical relationship between operating temperature and two-phase flow behavior in polymer electrolyte membrane (PEM) electrolyzers by investigating pore-scale gas bubble transport in the anode porous transport layer. Higher temperatures (80 °C vs 40 °C) result in a lower total bubble volume fraction and smaller bubble diameters, driven by enhanced water transport and increased bubble detachment rates. Abstract In this study, the effects of operating temperature on pore-scale gas bubble transport in a carbon-based anode porous transport layer (PTL) of a polymer electrolyte membrane (PEM) electrolyzer is revealed using operando X-ray computed tomography (CT). Higher temperature operation (80 °C compared to 40 °C) led to a lower total gas bubble volume fraction in the PTL (0.25 to 0.17; 32% lower), which is attributed to improved water transport and gas removal. Higher temperatures led to fewer bubbles in the PTL (13% less at 80 °C compared to 40 °C) as well as a greater occurrence of smaller bubbles (35% increase in skewness of the bubble size distribution), and this behavior is attributed to faster rates of nucleation and bubble detachment from the electrode. The formation of gas slugs is also observed in the anode channels at 60 °C and 80 °C, which is attributed to the faster detachment and coalescence of bubbles from the PTL/flow field interface. Advanced Science, Volume 12, Issue 44, November 27, 2025.

A Replicable and Generalizable Neuroimaging‐Based Indicator of Pain Sensitivity Across Individuals

Humans differ in their sensitivity to pain. With six large and diverse fMRI datasets (total N = 1046), this study finds that such individual differences in pain sensitivity can be tracked by fMRI responses to painful stimuli. A highly generalizable machine learning model is further built to predict pain sensitivity across all datasets and analgesic effects of different treatments. Abstract Revealing the neural underpinnings of pain sensitivity is crucial for understanding how the brain encodes individual differences in pain and advancing personalized pain treatments. Here, six large and diverse functional magnetic resonance imaging (fMRI) datasets (total N = 1046) are leveraged to uncover the neural mechanisms of pain sensitivity. Replicable and generalizable correlations are found between nociceptive‐evoked fMRI responses and pain sensitivity for laser heat, contact heat, and mechanical pains. These fMRI responses correlate more strongly with pain sensitivity than with tactile, auditory, and visual sensitivity. Moreover, a machine learning model is developed that accurately predicts not only pain sensitivity (r = 0.20∼0.56, ps < 0.05) but also analgesic effects of different treatments in healthy individuals (r = 0.17∼0.25, ps < 0.05). Notably, these findings are influenced considerably by sample sizes, requiring >200 for univariate whole brain correlation analysis and >150 for multivariate machine learning modeling. Altogether, this study demonstrates that fMRI activations encode pain sensitivity across various types of pain, thus facilitating interpretations of subjective pain reports and promoting more mechanistically informed investigations into pain physiology. Humans differ in their sensitivity to pain. With six large and diverse fMRI datasets (total N = 1046), this study finds that such individual differences in pain sensitivity can be tracked by fMRI responses to painful stimuli. A highly generalizable machine learning model is further built to predict pain sensitivity across all datasets and analgesic effects of different treatments. Abstract Revealing the neural underpinnings of pain sensitivity is crucial for understanding how the brain encodes individual differences in pain and advancing personalized pain treatments. Here, six large and diverse functional magnetic resonance imaging (fMRI) datasets (total N = 1046) are leveraged to uncover the neural mechanisms of pain sensitivity. Replicable and generalizable correlations are found between nociceptive-evoked fMRI responses and pain sensitivity for laser heat, contact heat, and mechanical pains. These fMRI responses correlate more strongly with pain sensitivity than with tactile, auditory, and visual sensitivity. Moreover, a machine learning model is developed that accurately predicts not only pain sensitivity (r = 0.20∼0.56, ps < 0.05) but also analgesic effects of different treatments in healthy individuals (r = 0.17∼0.25, ps < 0.05). Notably, these findings are influenced considerably by sample sizes, requiring >200 for univariate whole brain correlation analysis and >150 for multivariate machine learning modeling. Altogether, this study demonstrates that fMRI activations encode pain sensitivity across various types of pain, thus facilitating interpretations of subjective pain reports and promoting more mechanistically informed investigations into pain physiology. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Photobreeding Method for Direct Construction and Continuous Tuning of Strong Metal–Support Interactions at Room Temperature

A photobreeding strategy enables the room‐temperature construction of strong metal–support interactions (SMSI) on Zn0.8Cd0.2S, achieving both direct SMSI formation and continuous interfacial tuning. UV‐induced photoreduction of Zn2+ generates metallic Zn, which is subsequently encapsulated by CdS, offering tunable and enhanced catalytic performance. Abstract The construction of strong metal–support interactions (SMSI) is an effective strategy to enhance and control heterogeneous catalysts. However, conventional methods require pre‐synthesized metal‐loaded catalysts, followed by SMSI formation via high‐temperature treatment under oxidative/reductive atmospheres, adsorbate‐mediated treatment, and photo‐treatment, adding complexity to catalyst synthesis and hindering continuous interfacial tuning. In this work, a “photobreeding” method is employed to treat Zn0.8Cd0.2S, leveraging the UV‐induced photochromic reaction of ZnS to generate metallic Zn at room temperature, while CdS remains inert. Zn0.8Cd0.2S‐derived CdS directly encapsulates the generated Zn, enabling direct synthesis of SMSI catalysts without additional treatments. Furthermore, the interfacial properties can be continuously tuned by adjusting the photobreeding duration. The catalytic performance of SMSI catalysts synthesized via photobreeding exhibits a 3.1‐fold enhancement over the initial catalysts. To further boost performance, viologen, an electron mediator, is introduced to form a surface charge transfer complex. The resulting ZCS‐SMSI‐120/PV exhibits a hydrogen evolution rate of 48.7 mmol·g−1·h−1 without the use of noble metals, representing one of the highest values reported to date. This direct SMSI synthesis approach holds promise for applications in H2 production, CO2 reduction, biomass conversion, organic synthesis, and so on. A photobreeding strategy enables the room-temperature construction of strong metal–support interactions (SMSI) on Zn 0.8 Cd 0.2 S, achieving both direct SMSI formation and continuous interfacial tuning. UV-induced photoreduction of Zn 2+ generates metallic Zn, which is subsequently encapsulated by CdS, offering tunable and enhanced catalytic performance. Abstract The construction of strong metal–support interactions (SMSI) is an effective strategy to enhance and control heterogeneous catalysts. However, conventional methods require pre-synthesized metal-loaded catalysts, followed by SMSI formation via high-temperature treatment under oxidative/reductive atmospheres, adsorbate-mediated treatment, and photo-treatment, adding complexity to catalyst synthesis and hindering continuous interfacial tuning. In this work, a “photobreeding” method is employed to treat Zn 0.8 Cd 0.2 S, leveraging the UV-induced photochromic reaction of ZnS to generate metallic Zn at room temperature, while CdS remains inert. Zn 0.8 Cd 0.2 S-derived CdS directly encapsulates the generated Zn, enabling direct synthesis of SMSI catalysts without additional treatments. Furthermore, the interfacial properties can be continuously tuned by adjusting the photobreeding duration. The catalytic performance of SMSI catalysts synthesized via photobreeding exhibits a 3.1-fold enhancement over the initial catalysts. To further boost performance, viologen, an electron mediator, is introduced to form a surface charge transfer complex. The resulting ZCS-SMSI-120/PV exhibits a hydrogen evolution rate of 48.7 mmol·g −1 ·h −1 without the use of noble metals, representing one of the highest values reported to date. This direct SMSI synthesis approach holds promise for applications in H 2 production, CO 2 reduction, biomass conversion, organic synthesis, and so on. Advanced Science, Volume 12, Issue 44, November 27, 2025.

Switchbody, an Antigen‐Responsive Enzyme Switch Based on Antibody and Its Working Principle

This paper presents an antibody‐based enzyme switch, termed a “Switchbody”, which is fused with an enzyme‐derived fragment to the N‐terminus of an antibody. As its working principle, the fused fragment is trapped within the antibody and released upon antigen binding, leading to enzyme reconstitution and a subsequent increase in enzyme activity. This “Trap and Release” principle provides a framework for designing next‐generation enzyme switches. Abstract An enzyme switch, termed “Switchbody”, is developed by fusing an antibody with a fragment of a split enzyme for the precise regulation of enzyme activity in response to an antigen. A luciferase‐based Switchbody is engineered by fusing the NanoLuc luciferase fragment HiBiT to the N‐terminus of an antibody. The enzyme activity of the Switchbody increases upon the addition of an antigen in a dose‐dependent manner in the presence of the complementary fragment LgBiT and its substrate furimazine, demonstrating the potential of the luciferase‐based Switchbody as a biosensor. As its working principle, ELISA shows that the interaction between HiBiT and LgBiT is facilitated by antigen binding. Moreover, X‐ray crystallography and NMR reveal the heterogeneous trapped state of the HiBiT region and an increasing motility of HiBiT region upon antigen binding, respectively. MD simulations and luminescence measurements show that antigen disrupted the trapping of HiBiT in the antibody, enabling its release. By applying this “Trap and Release” principle to Protein M, an antibody‐binding protein, label‐free IgG antibodies are successfully converted into bioluminescent Switchbodies. This adaptable Switchbody platform has the potential to expand switching technology beyond luciferase to various other enzymes in the future. This paper presents an antibody-based enzyme switch, termed a “Switchbody”, which is fused with an enzyme-derived fragment to the N-terminus of an antibody. As its working principle, the fused fragment is trapped within the antibody and released upon antigen binding, leading to enzyme reconstitution and a subsequent increase in enzyme activity. This “Trap and Release” principle provides a framework for designing next-generation enzyme switches. Abstract An enzyme switch, termed “Switchbody”, is developed by fusing an antibody with a fragment of a split enzyme for the precise regulation of enzyme activity in response to an antigen. A luciferase-based Switchbody is engineered by fusing the NanoLuc luciferase fragment HiBiT to the N-terminus of an antibody. The enzyme activity of the Switchbody increases upon the addition of an antigen in a dose-dependent manner in the presence of the complementary fragment LgBiT and its substrate furimazine, demonstrating the potential of the luciferase-based Switchbody as a biosensor. As its working principle, ELISA shows that the interaction between HiBiT and LgBiT is facilitated by antigen binding. Moreover, X-ray crystallography and NMR reveal the heterogeneous trapped state of the HiBiT region and an increasing motility of HiBiT region upon antigen binding, respectively. MD simulations and luminescence measurements show that antigen disrupted the trapping of HiBiT in the antibody, enabling its release. By applying this “Trap and Release” principle to Protein M, an antibody-binding protein, label-free IgG antibodies are successfully converted into bioluminescent Switchbodies. This adaptable Switchbody platform has the potential to expand switching technology beyond luciferase to various other enzymes in the future. Advanced Science, Volume 12, Issue 44, November 27, 2025.

d‐Wave Fermi Surface Instability in the Nematic Phase of Two Monolayer FeSe/SrTiO3

Angle‐resolved photoemission spectroscopy reveals a d‐wave nematic order in two‐monolayer FeSe/SrTiO3, showing degenerate dxz/dyz bands at Γ but a pronounced splitting at M. This momentum‐dependent anisotropy identifies the nematicity as a d‐wave Fermi surface (Pomeranchuk) instability, highlighting 2D FeSe as a model platform to explore the interplay between nematicity and superconductivity. Abstract Nematicity, where electrons break rotational symmetry while preserving translational symmetry, is ubiquitous in strongly correlated quantum matters, including high‐Tc cuprates and iron‐based superconductors. A central question in nematicity is whether it is driven by Fermi surface instability in momentum space or orbital order (polarization) in real space, especially as nematicity intertwines with superconductivity. FeSe/SrTiO3 (STO), where nematicity occurs without long‐range magnetic order, is an ideal platform for studying the nature and origin of the electronic nematicity. Here, direct evidence of d‐wave nematic order in two monolayer FeSe/STO using angle‐resolved photoemission spectroscopy is presented, revealing a remarkable degeneracy of dxz and dyz bands at the Brillouin zone center, but a significant band separation at the zone corner. This momentum‐dependent nematicity demonstrates that nematicity in FeSe/STO originates from the d‐wave Fermi surface instability of the Pomeranchuk‐type, offering insights into the relationship between nematicity and superconductivity. The results establish 2D FeSe thin film as a powerful platform for investigating quantum physics under complex intertwinement. Angle-resolved photoemission spectroscopy reveals a d -wave nematic order in two-monolayer FeSe/SrTiO 3, showing degenerate d xz / d yz bands at Γ but a pronounced splitting at M. This momentum-dependent anisotropy identifies the nematicity as a d -wave Fermi surface (Pomeranchuk) instability, highlighting 2D FeSe as a model platform to explore the interplay between nematicity and superconductivity. Abstract Nematicity, where electrons break rotational symmetry while preserving translational symmetry, is ubiquitous in strongly correlated quantum matters, including high- T c cuprates and iron-based superconductors. A central question in nematicity is whether it is driven by Fermi surface instability in momentum space or orbital order (polarization) in real space, especially as nematicity intertwines with superconductivity. FeSe/SrTiO 3 (STO), where nematicity occurs without long-range magnetic order, is an ideal platform for studying the nature and origin of the electronic nematicity. Here, direct evidence of d -wave nematic order in two monolayer FeSe/STO using angle-resolved photoemission spectroscopy is presented, revealing a remarkable degeneracy of d xz and d yz bands at the Brillouin zone center, but a significant band separation at the zone corner. This momentum-dependent nematicity demonstrates that nematicity in FeSe/STO originates from the d -wave Fermi surface instability of the Pomeranchuk-type, offering insights into the relationship between nematicity and superconductivity. The results establish 2D FeSe thin film as a powerful platform for investigating quantum physics under complex intertwinement. Advanced Science, EarlyView.

Antiemesis Corticosteroids Potentiate Checkpoint Blockade Efficacy by Normalizing the Immune Microenvironment in Metastatic Murine Breast Cancer

Corticosteroids improve the efficacy of immune checkpoint blockade therapy in metastatic murine breast cancer. By normalizing the tumor immune microenvironment, corticosteroids reduce immunosuppressive signals, restore T‐cell function, and promote antitumor immune responses, resulting in enhanced tumor control. Abstract Glucocorticoid steroids are widely prescribed in oncology for managing treatment‐related side effects, though their use is discouraged in patients undergoing immune checkpoint blockade (ICB). Given the crucial role of steroids in supportive care, it is imperative to develop integrated strategies that do not compromise ICB therapy effectiveness. Here, protocols of dexamethasone resembling clinical antiemesis regimens are tested in murine models of ICB‐resistant breast cancer. Unexpectedly, dexamethasone enhanced the efficacy of ICB in models of primary cancer and spontaneous metastasis. Dexamethasone increased the volume of blood vessels within tumors, thereby facilitating lymphocyte infiltration and intratumor distribution. Additionally, dexamethasone depleted immunosuppressive cells and potentiated the capacity of ICB to enrich tumors of antigen‐recognizing cytotoxic lymphocytes. Importantly, it is found that dexamethasone does not abolish the functions of antigen‐naïve lymphocytes and has no effect on the activity of antigen‐experienced lymphocytes. These findings align with recent clinical guidelines and meta‐analyses, suggesting that dexamethasone deserves further exploration in ICB protocols to potentially benefit efficacy. Our study supports the notion that the current practice of avoiding short‐term glucocorticoid steroids in patients receiving ICB should be reconsidered toward enabling the use of steroids in clinical trials of new drug combinations. Corticosteroids improve the efficacy of immune checkpoint blockade therapy in metastatic murine breast cancer. By normalizing the tumor immune microenvironment, corticosteroids reduce immunosuppressive signals, restore T-cell function, and promote antitumor immune responses, resulting in enhanced tumor control. Abstract Glucocorticoid steroids are widely prescribed in oncology for managing treatment-related side effects, though their use is discouraged in patients undergoing immune checkpoint blockade (ICB). Given the crucial role of steroids in supportive care, it is imperative to develop integrated strategies that do not compromise ICB therapy effectiveness. Here, protocols of dexamethasone resembling clinical antiemesis regimens are tested in murine models of ICB-resistant breast cancer. Unexpectedly, dexamethasone enhanced the efficacy of ICB in models of primary cancer and spontaneous metastasis. Dexamethasone increased the volume of blood vessels within tumors, thereby facilitating lymphocyte infiltration and intratumor distribution. Additionally, dexamethasone depleted immunosuppressive cells and potentiated the capacity of ICB to enrich tumors of antigen-recognizing cytotoxic lymphocytes. Importantly, it is found that dexamethasone does not abolish the functions of antigen-naïve lymphocytes and has no effect on the activity of antigen-experienced lymphocytes. These findings align with recent clinical guidelines and meta-analyses, suggesting that dexamethasone deserves further exploration in ICB protocols to potentially benefit efficacy. Our study supports the notion that the current practice of avoiding short-term glucocorticoid steroids in patients receiving ICB should be reconsidered toward enabling the use of steroids in clinical trials of new drug combinations. Advanced Science, EarlyView.

Ultrafine Ru‐M Alloy@S Vacancy‐Rich MoS2 Nanosheets With Bimetallic Active Sites for Efficient Hydrogen Evolution in Alkaline and Acidic Media

A USMR synthesizes ultrafine RuCo alloy on S‐vacancy‐rich 1T phase MoS2. This method enables rapid precursor mixing, instantaneous reduction, and uniform alloy dispersion while creating S vacancies. The synergy between Ru‐Co sites and defective MoS2 optimizes hydrogen kinetics, achieving a low overpotential of 31 mV@10 mA·cm‐2 in acid, providing a scalable route for high‐performance dual‐site electrocatalysts. Abstract Developing efficient, scalable electrocatalysts for the hydrogen evolution reaction (HER) is crucial for industrial H2 production. Herein, ultrafine (≈1.7 nm) ruthenium‐cobalt (RuCo) alloys anchored on Sulfur‐vacancy‐rich 1T phase molybdenum disulfide (1T phase MoS2‐x) nanosheets (denoted as Ru2Co1‐4@E‐MoS2‐x) are synthesized via ultrasonic microreactor (USMR) technology. The USMR strategy concurrently achieves a reduced alloy size, accelerated Ru reduction kinetics, and improved metal dispersion, endowing the resulting catalysts with high metal loading and abundant accessible active sites. Experimental and theoretical analyses reveal that Co incorporation optimizes RuCo electronic structure and strengthens interfacial coupling with 1T phase MoS2‐x, lowering the Gibbs free energy of H* adsorption (ΔGH*) on both Ru and Co sites. This synergistic interaction establishes bimetallic active centers that overcome the adsorption–desorption trade‐off in single‐metal systems. In situ Raman spectroscopy further confirms that Co promotes water dissociation and hydrogen desorption at Ru sites under alkaline conditions. Consequently, Ru2Co1‐4@E‐MoS2‐x exhibits exceptional HER activity, achieving record‐low overpotentials of 31 mV in acidic and 36 mV in alkaline media at 10 mA·cm−2, significantly outperforming 20 wt% Pt/C (45 and 53 mV, respectively). Moreover, the USMR approach is universal, generating highly active RuM@E‐MoS2‐x catalysts (M = Fe, Ni, Cu). This work establishes a novel “bimetallic active sites/engineered carrier” paradigm for advanced electrocatalytic water splitting. A USMR synthesizes ultrafine RuCo alloy on S-vacancy-rich 1T phase MoS2. This method enables rapid precursor mixing, instantaneous reduction, and uniform alloy dispersion while creating S vacancies. The synergy between Ru-Co sites and defective MoS2 optimizes hydrogen kinetics, achieving a low overpotential of 31 mV@10 mA·cm-2 in acid, providing a scalable route for high-performance dual-site electrocatalysts. Abstract Developing efficient, scalable electrocatalysts for the hydrogen evolution reaction (HER) is crucial for industrial H 2 production. Herein, ultrafine (≈1.7 nm) ruthenium-cobalt (RuCo) alloys anchored on Sulfur-vacancy-rich 1T phase molybdenum disulfide (1T phase MoS 2-x ) nanosheets (denoted as Ru 2 Co 1 -4@E-MoS 2-x ) are synthesized via ultrasonic microreactor (USMR) technology. The USMR strategy concurrently achieves a reduced alloy size, accelerated Ru reduction kinetics, and improved metal dispersion, endowing the resulting catalysts with high metal loading and abundant accessible active sites. Experimental and theoretical analyses reveal that Co incorporation optimizes RuCo electronic structure and strengthens interfacial coupling with 1T phase MoS 2-x, lowering the Gibbs free energy of H * adsorption (ΔG H* ) on both Ru and Co sites. This synergistic interaction establishes bimetallic active centers that overcome the adsorption–desorption trade-off in single-metal systems. In situ Raman spectroscopy further confirms that Co promotes water dissociation and hydrogen desorption at Ru sites under alkaline conditions. Consequently, Ru 2 Co 1 -4@E-MoS 2-x exhibits exceptional HER activity, achieving record-low overpotentials of 31 mV in acidic and 36 mV in alkaline media at 10 mA·cm −2, significantly outperforming 20 wt% Pt/C (45 and 53 mV, respectively). Moreover, the USMR approach is universal, generating highly active RuM@E-MoS 2-x catalysts (M = Fe, Ni, Cu). This work establishes a novel “bimetallic active sites/engineered carrier” paradigm for advanced electrocatalytic water splitting. Advanced Science, EarlyView.

Characterizing Stage‐Specific Cellular Dynamics and Microenvironmental Remodeling in Lung Adenocarcinoma by Single‐Cell RNA Sequencing

Early tumors exhibit normoxic immune activation, while advanced stages show hypoxia‐driven immune exhaustion and suppression. Distinct cell populations—including STAT1‐driven exhausted CD8⁺ T cells, POSTN⁺ fibroblasts, FKBP11⁺ plasma cells, C5 tumor cells, and LGMN⁺ macrophages—cooperate to establish a hypoxia‐enriched, immunosuppressive microenvironment that promotes tumor progression Created with BioRender.com. Abstract Lung adenocarcinoma (LUAD) progression involves dynamic remodeling of the tumor microenvironment (TME). However, the stage‐specific dynamics of immune and stromal cell remodeling throughout LUAD progression remain incompletely understood. Here, the study systematically profiles the cellular composition and transcriptional states across multiple LUAD stages, integrating early‐stage patient specimens with publicly available datasets encompassing advanced‐stage disease. The analysis reveals a marked stage‐dependent shift from a proliferative and immune‐activated microenvironment in early LUAD to a hypoxia‐enriched and immunosuppressive landscape in advanced disease. A distinct hypoxia‐adapted epithelial tumor cell subpopulation (C5), exhibiting transcriptional features of metastasis, invasion, and hypoxia, and poor prognosis, is identified. Advanced LUAD featured immunosuppressive LGMN⁺ macrophages and STAT1‐driven exhausted CD8⁺ T cells. FKBP11⁺ plasma B cells exhibited exhaustion‐linked metabolic changes. POSTN⁺ CAFs emerged as central mediators of extracellular matrix (ECM) remodeling and immune exclusion. Collectively, the findings reveal a model of hypoxia‐driven functional convergence, in which distinct TME components co‐evolve toward phenotypes that collectively promote immune evasion, matrix remodeling, and tumor progression. These findings may provide insights into stage‐specific cellular dynamics and highlight promising therapeutic targets for precision immunotherapy strategies. Early tumors exhibit normoxic immune activation, while advanced stages show hypoxia-driven immune exhaustion and suppression. Distinct cell populations—including STAT1-driven exhausted CD8⁺ T cells, POSTN⁺ fibroblasts, FKBP11⁺ plasma cells, C5 tumor cells, and LGMN⁺ macrophages—cooperate to establish a hypoxia-enriched, immunosuppressive microenvironment that promotes tumor progression Created with BioRender.com. Abstract Lung adenocarcinoma (LUAD) progression involves dynamic remodeling of the tumor microenvironment (TME). However, the stage-specific dynamics of immune and stromal cell remodeling throughout LUAD progression remain incompletely understood. Here, the study systematically profiles the cellular composition and transcriptional states across multiple LUAD stages, integrating early-stage patient specimens with publicly available datasets encompassing advanced-stage disease. The analysis reveals a marked stage-dependent shift from a proliferative and immune-activated microenvironment in early LUAD to a hypoxia-enriched and immunosuppressive landscape in advanced disease. A distinct hypoxia-adapted epithelial tumor cell subpopulation (C5), exhibiting transcriptional features of metastasis, invasion, and hypoxia, and poor prognosis, is identified. Advanced LUAD featured immunosuppressive LGMN⁺ macrophages and STAT1-driven exhausted CD8⁺ T cells. FKBP11⁺ plasma B cells exhibited exhaustion-linked metabolic changes. POSTN⁺ CAFs emerged as central mediators of extracellular matrix (ECM) remodeling and immune exclusion. Collectively, the findings reveal a model of hypoxia-driven functional convergence, in which distinct TME components co-evolve toward phenotypes that collectively promote immune evasion, matrix remodeling, and tumor progression. These findings may provide insights into stage-specific cellular dynamics and highlight promising therapeutic targets for precision immunotherapy strategies. Advanced Science, EarlyView.

Label‐Free Leukocyte Biophysical Profiling Using Impedance‐Deformability Cytometry for Rapid Cardiovascular Risk Stratification

This study presents an impedance‐based single‐cell profiling platform that quantifies the electrical and mechanical properties of neutrophils across in vitro, in vivo, and clinical samples. The approach reveals distinct biophysical alterations associated with type 2 diabetes (T2DM) and cardiovascular complications, suggesting its potential utility for functional, label‐free assessment of immune dysregulation and cardiovascular risk stratification in T2DM. Abstract Type 2 diabetes mellitus (T2DM) presents a global health burden with cardiovascular disease (CVD) as its leading cause of mortality. A rapid clinical‐adaptable microfluidic workflow for label‐free CVD risk profiling based on neutrophil biophysical abnormalities is developed. This high‐throughput single cell (>1,000 cells min−1) “electro‐mechano‐phenotyping” method integrates Uniform Manifold Approximation and Projection analysis to assess leukocyte biophysical changes (size, deformability, and impedance properties) linked to inflammation, thrombosis, and hyperglycemia in vitro, and in diabetic and diabetic atherosclerosis‐prone mouse models. In a clinical study of healthy, pre‐diabetes, diabetes, and diabetic patients with CVD (DM‐CVD) subjects (n = 10–11 per group), DM‐CVD neutrophils exhibited a distinct impedance signature and pro‐inflammatory transcriptomic profile marked by cytoskeletal dysregulation and altered RhoA signaling. Principal component analysis (area under the curve = 0.971) identifies individuals with vascular dysfunction exhibiting increased carotid intima‐media thickness and reduced reactive hyperemia index. These findings support impedance‐based neutrophil profiling as a promising, cost‐effective strategy for cardiovascular risk stratification in T2DM. This study presents an impedance-based single-cell profiling platform that quantifies the electrical and mechanical properties of neutrophils across in vitro, in vivo, and clinical samples. The approach reveals distinct biophysical alterations associated with type 2 diabetes (T2DM) and cardiovascular complications, suggesting its potential utility for functional, label-free assessment of immune dysregulation and cardiovascular risk stratification in T2DM. Abstract Type 2 diabetes mellitus (T2DM) presents a global health burden with cardiovascular disease (CVD) as its leading cause of mortality. A rapid clinical-adaptable microfluidic workflow for label-free CVD risk profiling based on neutrophil biophysical abnormalities is developed. This high-throughput single cell (>1,000 cells min −1 ) “electro-mechano-phenotyping” method integrates Uniform Manifold Approximation and Projection analysis to assess leukocyte biophysical changes (size, deformability, and impedance properties) linked to inflammation, thrombosis, and hyperglycemia in vitro, and in diabetic and diabetic atherosclerosis-prone mouse models. In a clinical study of healthy, pre-diabetes, diabetes, and diabetic patients with CVD (DM-CVD) subjects ( n = 10–11 per group), DM-CVD neutrophils exhibited a distinct impedance signature and pro-inflammatory transcriptomic profile marked by cytoskeletal dysregulation and altered RhoA signaling. Principal component analysis (area under the curve = 0.971) identifies individuals with vascular dysfunction exhibiting increased carotid intima-media thickness and reduced reactive hyperemia index. These findings support impedance-based neutrophil profiling as a promising, cost-effective strategy for cardiovascular risk stratification in T2DM. Advanced Science, EarlyView.

A Sub‐1 Nm Cluster Chains‐enhanced Poly(ethylene oxide) Electrolyte for an All‐solid‐State Lithium Metal Battery with a Long Cycling Lifespan

Sub‐1 nm inorganic cluster chain with cation vacancies optimize PEO electrolytes by eliminating Li+ migration barriers and constructing 3D ion transport networks, while in situ c‐AFM reveals dynamic transport mechanisms, enabling high‐performance all‐solid‐state batteries. Abstract Flexible composite polymer electrolytes (CPEs) are promising candidates for high‐energy all‐solid‐state lithium metal batteries, owing to their superior processability, excellent electrochemical performance, and enhanced safety. Nevertheless, conventional CPEs face challenges such as lithium‐ion blocking and aggregation from inert fillers, hindering ion transport. To address these issues, highly dispersed materials need optimization in polymer matrices. In this study, a new strategy is introduced to introduce sub‐1 nm inorganic cluster chains into poly(ethylene oxide) based electrolytes. These ultra‐thin highly dispersed cluster chains eliminated the Li blocking region and aggregation‐induced barrier, formed a 3D network, and realized the efficient conductivity of Li+. By engineering La vacancies into the cluster chains of Ta‐doped LaOOH crystals, low‐energy migration pathways are created. This optimized electrolyte achieves the ionic conductivity of 0.65 mS cm−1 at 60 °C and the lithium transference number of 0.47. Electrochemical testing shows outstanding stability: Li||LTPE||Li symmetric cells maintain stable Li plating and stripping for 2000 h, and LiFePO4||LTPE||Li cells achieve 138.5 mAh g−1 with 93.4% capacity retention after 2000 cycles at 2C. Furthermore, the pioneering application of in situ conductive atomic force microscopy enables unprecedented characterization of temperature‐dependent morphological evolution and heterogeneous ion transport dynamics in solid electrolytes. Sub-1 nm inorganic cluster chain with cation vacancies optimize PEO electrolytes by eliminating Li + migration barriers and constructing 3D ion transport networks, while in situ c-AFM reveals dynamic transport mechanisms, enabling high-performance all-solid-state batteries. Abstract Flexible composite polymer electrolytes (CPEs) are promising candidates for high-energy all-solid-state lithium metal batteries, owing to their superior processability, excellent electrochemical performance, and enhanced safety. Nevertheless, conventional CPEs face challenges such as lithium-ion blocking and aggregation from inert fillers, hindering ion transport. To address these issues, highly dispersed materials need optimization in polymer matrices. In this study, a new strategy is introduced to introduce sub-1 nm inorganic cluster chains into poly(ethylene oxide) based electrolytes. These ultra-thin highly dispersed cluster chains eliminated the Li blocking region and aggregation-induced barrier, formed a 3D network, and realized the efficient conductivity of Li +. By engineering La vacancies into the cluster chains of Ta-doped LaOOH crystals, low-energy migration pathways are created. This optimized electrolyte achieves the ionic conductivity of 0.65 mS cm − 1 at 60 °C and the lithium transference number of 0.47. Electrochemical testing shows outstanding stability: Li||LTPE||Li symmetric cells maintain stable Li plating and stripping for 2000 h, and LiFePO 4 ||LTPE||Li cells achieve 138.5 mAh g −1 with 93.4% capacity retention after 2000 cycles at 2C. Furthermore, the pioneering application of in situ conductive atomic force microscopy enables unprecedented characterization of temperature-dependent morphological evolution and heterogeneous ion transport dynamics in solid electrolytes. Advanced Science, EarlyView.

Hierarchically Porous Nitrogen‐Doped Carbon with High Conductivity for Rapid and Efficient Cr(VI) Reduction

The d‐PNC(1100, 10%) catalyst, synthesized via a zinc‐based ionic liquid self‐sacrificing pore‐forming strategy to create a defect‐rich, hierarchical, nitrogen‐doped porous structure, enhances conductivity, promotes rapid mass transfer and synergistic catalytic activity, driving efficient Cr(VI) reduction in OA solution to generate Cr(III)‐OA complexes. Abstract Carbon‐based materials derived from metal–organic frameworks typically exhibit microporous structures and low conductivity, which significantly limit their catalytic activity. Herein, an effective strategy to prepare dodecahedral hierarchical porous nitrogen‐doped carbon‐based composites (d‐PNC) by using ZIF‐8 encapsulated with ionic liquid as pyrolysis precursors for efficient Cr(VI) reduction is developed. The encapsulated ionic liquid helps to precisely regulate the hierarchically porous structure in d‐PNC. This hierarchically porous structure not only creates a favorable reaction microenvironment, facilitating the mass transfer of Cr species and their interaction with active sites, but also enhancing the conductivity of d‐PNC and consequently accelerating the electron transfer of •CO2− radicals to Cr species, thereby speeding up the reduction process of Cr(VI). Additionally, with the calcination temperature increasing, the content of defective C increases, and N species progressively transforms into graphitic‐center N (N3). Density functional theory calculations reveal that the defective C active center substantially decreases the free energy change of the rate‐determining step (from Cr(IV) to Cr(III)) through the synergistic effect of N3. Given these outstanding characteristics, the optimized d‐PNC material can completely reduce Cr(VI) (333.3 mg g−1) in an oxalic acid solution within 2 min, outperforming its counterparts without a hierarchical structure and those calcined at significantly lower temperatures. The d-PNC(1100, 10%) catalyst, synthesized via a zinc-based ionic liquid self-sacrificing pore-forming strategy to create a defect-rich, hierarchical, nitrogen-doped porous structure, enhances conductivity, promotes rapid mass transfer and synergistic catalytic activity, driving efficient Cr(VI) reduction in OA solution to generate Cr(III)-OA complexes. Abstract Carbon-based materials derived from metal–organic frameworks typically exhibit microporous structures and low conductivity, which significantly limit their catalytic activity. Herein, an effective strategy to prepare dodecahedral hierarchical porous nitrogen-doped carbon-based composites (d-PNC) by using ZIF-8 encapsulated with ionic liquid as pyrolysis precursors for efficient Cr(VI) reduction is developed. The encapsulated ionic liquid helps to precisely regulate the hierarchically porous structure in d-PNC. This hierarchically porous structure not only creates a favorable reaction microenvironment, facilitating the mass transfer of Cr species and their interaction with active sites, but also enhancing the conductivity of d-PNC and consequently accelerating the electron transfer of •CO 2 − radicals to Cr species, thereby speeding up the reduction process of Cr(VI). Additionally, with the calcination temperature increasing, the content of defective C increases, and N species progressively transforms into graphitic-center N (N3). Density functional theory calculations reveal that the defective C active center substantially decreases the free energy change of the rate-determining step (from Cr(IV) to Cr(III)) through the synergistic effect of N3. Given these outstanding characteristics, the optimized d-PNC material can completely reduce Cr(VI) (333.3 mg g −1 ) in an oxalic acid solution within 2 min, outperforming its counterparts without a hierarchical structure and those calcined at significantly lower temperatures. Advanced Science, EarlyView.

NIR Ratiometric Fluorescent Antibody‐Drug Conjugate for Metastatic Ovarian Cancer Theranostics and Treatment Response Monitoring

In vivo optical imaging enhances antibody‐drug conjugate (ADC) optimization by enabling real‐time monitoring of stimulus‐responsive drug behavior. We report n501‐CYMMAF, a ratiometric theranostic with strong target affinity and low‐dose efficacy for ovarian metastasis. Its dual therapeutic and imaging functions allow in‐situ tracking of treatment‐evading cells, offering insights into recurrence and treatment endpoints. n501‐CYMMAF exemplifies next‐generation precision metastasis theranostics. Abstract In vivo optical imaging advances antibody‐drug conjugate (ADC) optimization by enabling real‐time monitoring of biological stimulus‐responsive drug behavior. Ratiometric probes, incorporating orthogonal wavelength‐encoded multicolor detection and stimuli‐cleavable linkages, are preferred over single‐color strategies. Here, the synthesis of n501‐CYMMAF (cyanine‐decorated Monomethylauristatin F) is described as a novel ratiometric theranostic agent for dual efficacy in ovarian metastasis treatment and in situ treatment response monitoring. With low‐dose administration (2.5 mg kg−1), exceptional target affinity (EC50(n501‐CYMMAF) = 1.17 nm), and favorable biosafety (delivery to tumor‐parts only), n501‐CYMMAF enables experimental verification of treatment‐evading metastatic cell populations through in situ fluorescent tracking, providing crucial insights into tumor recurrence pathways and judgement of treatment terminal point. In general, n501‐CYMMAF represents a prototype for next‐generation smart theranostics, integrating treatment and endpoint assessment to offer a platform for precision metastasis management. In vivo optical imaging enhances antibody-drug conjugate (ADC) optimization by enabling real-time monitoring of stimulus-responsive drug behavior. We report n501-CYMMAF, a ratiometric theranostic with strong target affinity and low-dose efficacy for ovarian metastasis. Its dual therapeutic and imaging functions allow in-situ tracking of treatment-evading cells, offering insights into recurrence and treatment endpoints. n501-CYMMAF exemplifies next-generation precision metastasis theranostics. Abstract In vivo optical imaging advances antibody-drug conjugate (ADC) optimization by enabling real-time monitoring of biological stimulus-responsive drug behavior. Ratiometric probes, incorporating orthogonal wavelength-encoded multicolor detection and stimuli-cleavable linkages, are preferred over single-color strategies. Here, the synthesis of n501-CYMMAF (cyanine-decorated Monomethylauristatin F) is described as a novel ratiometric theranostic agent for dual efficacy in ovarian metastasis treatment and in situ treatment response monitoring. With low-dose administration (2.5 mg kg −1 ), exceptional target affinity (EC 50(n501-CYMMAF) = 1.17 n m ), and favorable biosafety (delivery to tumor-parts only), n501-CYMMAF enables experimental verification of treatment-evading metastatic cell populations through in situ fluorescent tracking, providing crucial insights into tumor recurrence pathways and judgement of treatment terminal point. In general, n501-CYMMAF represents a prototype for next-generation smart theranostics, integrating treatment and endpoint assessment to offer a platform for precision metastasis management. Advanced Science, EarlyView.