Syrosingopine enhances immune checkpoint blockade efficacy by inhibition of MCTs and metabolic reprogramming in triple-negative breast cancer.

Immune checkpoint blockade (ICB) provides limited benefit in triple-negative breast cancer (TNBC), partly due to a lactate-rich, immunosuppressive tumor microenvironment (TME). Integrative bulk and single-cell transcriptomics, corroborated by tissue analyses, identify MCT4 as the predominant lactate transporter in TNBC, while supporting a context-dependent contribution of MCT1, and reveal an inverse association between MCT4 and intratumoral CD8+ T cells. We therefore tested whether inhibition of monocarboxylate transporters could recondition the TME. The repurposed agent syrosingopine, a dual MCT1/MCT4 inhibitor, consistently blocked lactate export across MCT1+ and MCT4+ models without altering transporter/LDH abundance, and reduced tumor cell PD-L1 while restoring T-cell effector function. Syrosingopine also sensitized tumor cells to NK-cell cytotoxicity without detectable toxicity in immune cells. In immunocompetent TNBC models, syrosingopine synergized with anti-PD-1 to suppress tumor growth, remodel the immune landscape, and prolong survival, while genetic perturbation of MCTs recapitulated key metabolic and immunologic phenotypes. These findings identify tumor lactate export as an important metabolic barrier to antitumor immunity in TNBC and support MCT-targeted lactate transport inhibition as a promising strategy to reprogram the TME and improve immunotherapeutic efficacy.