STING 与 TOX 协同抑制 HO-1 表达，触发肿瘤浸润 CD8+ T 细胞铁死亡及免疫治疗耐药

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.