MCT1 Inhibition Remodels the Tumor Immune Microenvironment for Enhanced Cancer Immunotherapy

Despite advances in cancer immunotherapies such as immune checkpoint blockade (ICB), durable patient responses remain constrained, which is largely due to the highly suppressive tumor immune microenvironment (TIME). In this study, by analyzing cohorts of patients with pan-cancer and experimental validation, we found that monocarboxylate transporter 1 (MCT1) expression is broadly upregulated in malignant and myeloid compartments within the TIME. MCT1 expression is also associated with worse survival, a suppressive TIME state, and poor treatment response to ICB therapy. Functionally, MCT1-mediated lactate uptake by tumor cells and tumor-associated macrophages (TAM) suppresses CD8+ T-cell activation and cytotoxicity in the ex vivo coculture models. Mechanistically, lactate exposure and uptake via MCT1 in tumor cells and TAMs induce IL10 production, which contributes to the inhibition of the antitumor response of CD8+ T cells. Moreover, in MC38 and LLC mouse cancer models, pharmacologic MCT1 inhibition reprograms the immunosuppressive myeloid populations, improves CD8+ T-cell infiltration and function, and triggers tumor regression. Therefore, these results indicate that MCT1 has the potential to be a biomarker for patients across cancer types and to be a promising therapeutic target for enhanced cancer immunotherapy.