STING synergizes with TOX suppressing HO-1 expression to trigger ferroptosis in tumor-infiltrating CD8+ T cell and immunotherapy resistance

CD8+ T cell abundance within the tumor microenvironment is a critical determinant of immunotherapy efficacy. Here we show that CD8⁺ T cells lacking STING or TOX display markedly improved antitumor activity, with enhanced tumor infiltration and elevated IFN-γ and granzyme B production. These STING or TOX deficient cells exhibit a stem-like transcriptional state and resist ferroptosis by suppressing lipid peroxidation pathways while promoting mitochondrial biogenesis. Mechanistically, STING and TOX form a positive regulatory loop that represses HO-1 expression, leading to iron accumulation, mitochondrial oxidative stress, and ferroptosis in tumor-infiltrating CD8⁺ T cells. We further identify lactate as a microenvironmental trigger of STING–TOX–HO-1-mediated CD8+ T-cell ferroptosis. In mouse tumor models, engineered STING/TOX-deficient CD8⁺ T cells synergize with immune checkpoint blockade, chemotherapy, or STING agonist to enhance tumor control. These findings reveal a central pathway governing CD8⁺ T-cell ferroptosis in tumors and suggest therapeutic strategies to overcome immunotherapy resistance. CD8⁺ T cell abundance in the tumor microenvironment is critical for immunotherapy success. This study shows that the STING–TOX axis suppresses CD8⁺ T cell antitumor activity by inducing ferroptosis. STING–TOX-deficient CD8⁺ T cells enhance outcomes when combined with checkpoint blockade or chemotherapy.