Navigating the role of protein lactylation in prostate cancer and its implications for immunotherapy

Abstract

Prostate cancer is an aggressive malignancy with high prevalence and significant mortality, characterized by its remarkable metabolic adaptability and immune complexity. Emerging evidence has highlighted the critical role of post-translational modifications (PTMs) in cancer biology, with protein lactylation gaining attention as a novel PTM with profound implications. Lactylation, derived from lactate, links the altered metabolic processes of tumor cells to diverse cellular functions, including epigenetic regulation and protein dynamics. It significantly influences tumor progression, immune evasion, and therapeutic resistance by modulating key immune cells within the tumor microenvironment. The immunosuppressive conditions created by lactate and lactylation favor tumor survival in prostate cancer. Thus, targeting lactylation offers innovative strategies for treating prostate cancer. By leveraging lactylation modulation, particularly in combination with immune checkpoint inhibitors, there is potential to enhance anti-tumor immune responses and improve treatment outcomes. This review explores the intersection of metabolic alterations and immune modulation, underscoring lactylation as a promising therapeutic avenue in prostate cancer.

Keywords: immune checkpoints; immunotherapy; lactylation; prostate cancer; tumor microenvironment.

Figure 1

Lactylation of histone proteins and non-histone proteins. This schematic illustrates the process of lactylation, a post-translational modification where lactate is covalently added to lysine (Lys) residues in proteins. On the left, lactylation of histone proteins is shown, where lactate, produced from glucose metabolism, is transferred to lysine residues in the histone tails, influencing chromatin structure and gene expression. The right panel depicts the lactylation of non-histone proteins, where lactate binds to lysine residues of non-histone proteins, altering their function, stability, and interactions. In both cases, lactate modification can significantly impact protein function and cellular processes such as gene regulation, immune response, and tumor progression. The diagram emphasizes the role of lactate metabolism in regulating protein modifications and their implications in various biological contexts.

Figure 2

Lactate and lactylation promote prostate cancer progression. Lactate is transported into prostate cancer cells via monocarboxylate transporter 1 (MCT1) and exported to the extracellular space by MCT4. To meet the high energy demands during progression, prostate cancer cells primarily rely on glycolysis, which generates pyruvate. Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate. Elevated lactate levels lead to both histone and non-histone lactylation, which subsequently promotes prostate cancer progression. Reducing lactate levels and inhibiting lactylation, especially in combination with immunotherapy, synergistically suppress prostate cancer progression.

Figure 3

Lactate and lactylation regulate T cell-mediated immune response in prostate cancer. Lactate, a key metabolite in the tumor microenvironment (TME), plays a crucial role in shaping T cell function and immune evasion in prostate cancer. Within T cells, lactate is transported via SLC5A12 (in CD4⁺ T cells) and SLC16A1 (MCT1) (in CD8⁺ T cells), affecting their metabolic activity and immune responses. Increased lactate accumulation inhibits glycolysis in CD4⁺ T cells, impairing their ability to exit inflammatory sites and thereby contributing to immune suppression. Meanwhile, cancer-associated fibroblast (CAF)-derived lactate promotes regulatory T cell (Treg) expansion, creating an immunosuppressive TME that sustains prostate cancer progression. Lactylation, a post-translational modification influenced by lactate metabolism, occurs on histones H3K18 and H3K9 in CD8⁺ T cells, altering gene transcription and leading to T cell exhaustion. This process weakens cytotoxic T cell function, enhancing tumor immune escape and contributing to immune resistance against checkpoint inhibitors like anti-PD-L1 therapy. Overall, lactate and lactylation-mediated metabolic reprogramming promote prostate cancer progression, highlighting potential therapeutic targets for overcoming immunosuppression and enhancing T cell-mediated tumor clearance.