Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity PMID: 39592880

ADC Targets in Oncology

2026-04-10

Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity

Nat Aging. 2024 Dec;4(12):1828-1844. doi: 10.1038/s43587-024-00746-5.

Siyu Pei ^# ¹ ² , Xiuyu Deng ^# ² , Ruirui Yang ^# ³ , Hui Wang ^# ¹ , Jian-Hong Shi ^# ⁴ , Xueqing Wang ² , Jia Huang ¹ , Yu Tian ¹ , Rongjing Wang ² , Sulin Zhang ³ , Hui Hou ³ , Jing Xu ² , Qingcheng Zhu ² , Huan Huang ² , Jialing Ye ² , Cong-Yi Wang ⁵ , Wei Lu ² , Qingquan Luo ⁶ , Zhi-Yu Ni ⁷ ⁸ ⁹ , Mingyue Zheng ¹⁰ , Yichuan Xiao ¹¹

Affiliations

1. Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
3. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
4. Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China.
5. Department of Respiratory and Critical Care Medicine, Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
6. Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
7. Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding, China. [email protected].
8. Affiliated Hospital of Hebei Engineering University, Handan, China. [email protected].
9. Clinical Medical College, Hebei University of Engineering, Handan, China. [email protected].
10. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
11. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
# Contributed equally.

Abstract

Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8⁺ tissue resident memory T (T_RM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8⁺ T cells, which we also observed in human lung adenocarcinoma. We further identified that the Apoptosis regulator BFAR was highly enriched in aged CD8⁺ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated T_RM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8⁺ T cells by restoring T_RM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8⁺ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced T_RM restriction as a key mechanism causing aged CD8⁺ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.