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

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

  • Nat Commun. 2026 Feb 9;17(1):2543. doi: 10.1038/s41467-026-69350-y.
Qian Zhu # 1 2,  Jun-Bao Zhang # 1 2,  Cai-Ping Nie # 1 2,  Xiu-Feng Liu # 1 2,  Liang-Ping Zhan # 1 2,  Ming Li 1 2,  Xi-Liang Zeng 1,  Jia He 1 2,  He Huang 1 3,  Xiao-Jun Xia 1,  Song Gao 1,  Xiao-Shi Zhang 1 2,  Jiang Li 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
  • 2 Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Department of Gynecological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. [email protected].
  • 5 Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41663385 DOI: 10.1038/s41467-026-69350-y
Abstract

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.

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