Combined GPR81 Blockade and STING Agonism Restore CD8⁺ T Cell–Mediated Tumor Control in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) creates an immunosuppressive tumor microenvironment (TME) that limits the efficacy of checkpoint immunotherapy. Tumor-derived lactate activates GPR81 signaling on tumor-associated macrophages (TAMs), while the STING pathway, which normally drives innate immune activation, remains suppressed, together maintaining TAMs in an immunosuppressive state and limiting CD8⁺ T cell activity. This study aims to test whether combined GPR81 blockade and STING activation can synergistically repolarize TAMs and restore CD8⁺ T cell–mediated tumor control. Using a syngeneic 4T1 mouse model of TNBC, we will compare vehicle, single-agent, and combination treatment groups, alongside genetic GPR81 deletion and CD8⁺ T cell depletion to establish pathway specificity. We predict combination therapy will produce greater macrophage repolarization, CD8⁺ T cell infiltration, and tumor regression than either agent alone. These findings would support dual metabolic and innate immune targeting as a strategy to overcome immunotherapy resistance in breast cancer.