Lactate and lactylation in cancer: drivers of immune suppression and microenvironmental reprogramming

Lactate, a key metabolite of the Warburg effect, plays a central role in shaping multiple hallmarks of cancer. Through lactate shuttling and engagement with specific receptors, it activates downstream signaling pathways that remodel the tumor microenvironment (TME) and facilitate tumor progression. More recently, lysine lactylation-an emerging post-translational modification derived from lactate-has been identified as a crucial epigenetic mechanism that links altered tumor metabolism with transcriptional regulation. Lactylation has been implicated in promoting tumor proliferation, metastasis, stemness maintenance, immune evasion, and therapeutic resistance across various cancer types. Both tumor and immune cells undergo lactylation, which modulates gene expression and contributes to the immunosuppressive landscape of the TME. Targeting lactate production and transport has shown promise in suppressing tumor growth and enhancing immunotherapeutic efficacy. In this review, we comprehensively discuss the functional roles and underlying mechanisms of lactate and lactylation in cancer progression, with a particular focus on their impact within the TME. We also highlight recent advances in targeting these metabolic processes as potential therapeutic strategies, aiming to provide new perspectives for improving cancer treatment outcomes.