Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy

Lactate, once deemed a metabolic waste, emerges as a central regulator of cancer progression. This review elucidates how lactate and its epigenetic derivative, protein lactylation, orchestrate tumor metabolism, immune suppression, and therapeutic resistance. It further highlights evolving strategies that target lactate metabolism and lactylation to enhance cancer immunotherapy and clinical translation. ABSTRACT Lactate has evolved from being regarded as a byproduct of glycolysis to a pivotal regulator of cancer metabolism and signaling. The Warburg effect underscores how elevated lactate production meets the biosynthetic demands of highly proliferative cancer cells, while shaping an immunosuppressive tumor microenvironment (TME) that supports cancer growth and metastasis. The discovery of lactylation, a novel post‐translational modification, has further expanded the conceptual landscape, revealing how lactate serves as both a metabolite and a signaling molecule that couples metabolic reprogramming with gene regulation. This review delineates how lactate dynamically shuttles through the TME and boosts cancer malignancy, including proliferation, metastasis, drug resistance, and immune evasion. Also, this review integrates and discusses how lactate‐driven lactylation bridges metabolic and epigenetic control. Furthermore, emerging therapeutic strategies targeting lactate metabolism and lactylation are summarized, revealing their promise in cancer immunotherapy. Collectively, a comprehensive perspective is provided on the multifaceted roles of lactate and lactylation in cancer biology and, more importantly, highlights potential translational avenues for clinical applications. Lactate, once deemed a metabolic waste, emerges as a central regulator of cancer progression. This review elucidates how lactate and its epigenetic derivative, protein lactylation, orchestrate tumor metabolism, immune suppression, and therapeutic resistance. It further highlights evolving strategies that target lactate metabolism and lactylation to enhance cancer immunotherapy and clinical translation. ABSTRACT Lactate has evolved from being regarded as a byproduct of glycolysis to a pivotal regulator of cancer metabolism and signaling. The Warburg effect underscores how elevated lactate production meets the biosynthetic demands of highly proliferative cancer cells, while shaping an immunosuppressive tumor microenvironment (TME) that supports cancer growth and metastasis. The discovery of lactylation, a novel post-translational modification, has further expanded the conceptual landscape, revealing how lactate serves as both a metabolite and a signaling molecule that couples metabolic reprogramming with gene regulation. This review delineates how lactate dynamically shuttles through the TME and boosts cancer malignancy, including proliferation, metastasis, drug resistance, and immune evasion. Also, this review integrates and discusses how lactate-driven lactylation bridges metabolic and epigenetic control. Furthermore, emerging therapeutic strategies targeting lactate metabolism and lactylation are summarized, revealing their promise in cancer immunotherapy. Collectively, a comprehensive perspective is provided on the multifaceted roles of lactate and lactylation in cancer biology and, more importantly, highlights potential translational avenues for clinical applications. Advanced Science, EarlyView.