乳酸驱动的免疫代谢重编程在头颈部鳞状细胞癌中的研究进展及展望OA

Head and neck squamous cell carcinoma(HNSCC)is a highly heterogeneous and profoundly immunosuppressive malignancy.Current immunotherapeutic approaches continue to face limitations regarding overall response rates and sustained efficacy.Emerging evidence highlights tumor immune-metabolic reprogramming as a pivotal mechanism underlying immune evasion,with dysregulation of lactate metabolism emerging as a central focus of research.Lactate,a key metabolite derived from aberrant glycolysis in tumor cells,serves not only as the major driver of acidosis in the tumor microenvironment(TME)but also exhibits the dual properties of an"oncometabolite"and a bioactive signaling molecule.It plays a central regulatory role in promoting immunosuppression and tumor progression.Significant advances have been made in recent years in the study of lactate metabolism in head and neck squamous cell carcinoma.At the level of immune regulation,lactate suppresses glucose uptake and cytotoxic function in CD8⁺ T cells,impairs the maturation of dendritic cells(DCs),induces high expression of FOXP3 in regulatory T cells(Tregs)to sustain their immunosuppressive function,and drives the polarization of tumor-associated macrophages(TAMs)toward the M2 phenotype,collectively establishing a profoundly immunosuppressive state.Moreover,high lactate levels further remodel the tumor immune landscape and promote immune escape by modulating histone acetylation,maintaining tumor cell stemness,and activating multiple signaling pathways.Regarding prognostic biomarkers,this review explores the expression patterns of key lactate metabolism molecules[e.g.,lactate dehydrogenase A(LDHA),monocarboxylate transporter(MCT)1,and MCT4]and associated hub genes(e.g.,PYGL and APP)in HNSCC.Their frequent overexpression,which correlates closely with patient prognosis,highlights their translational potential as prognostic indicators.In terms of therapeutic strategies,targeting lactate metabolism has emerged as an important direction.Inhibitors of lactate production or transport(e.g.,LDHA or MCT inhibitors)can reduce lactate accumulation,reverse the metabolic advantage of tumors,and improve the immune microenvironment.When combined with immune checkpoint inhibitors,they effectively promote the conversion of"cold"tumors into"hot"tumors.Furthermore,the synergistic application of epigenetic modulators,novel biomaterials,and nanodelivery technologies enables precise reprogramming of lactate-related signaling pathways,demonstrating promising potential in preclinical studies to enhance the efficacy of immunotherapy.In conclusion,this review provides a comprehensive analysis of the lactate-mediated"metabolite-immune axis"in HNSCC,elucidating its key mechanisms and exploring precision therapeutic strategies that combine targeted modulation of lactate pathways with immune-based interventions.It aims to establish a solid theoretical foundation and propose novel research directions to facilitate clinical translation,ultimately paving the way for innovative combination therapies to improve outcomes for HNSCC patients.