Hyo-Jung Lee^1,2, Kwon-Ho Song³, Se Jin Oh^1,2,4, Suyeon Kim^1,2,4, Eunho Cho^1,2,4, Jungwon Kim^1,2, Yun gyu Park^1,2, Kyung-Mi Lee^1,2, Cassian Yee^5,6, Seung-Hwa Song^1,2, Suhwan Chang^7,8, Jungmin Choi^2,4, Sang Taek Jung^2,4 & Tae Woo Kim^1,2,4,9,*

¹Department of Biochemistry and Molecular Biology, Korea university College of Medicine, Seoul 02841, Republic of Korea. ²Department of Biomedical Science, Korea university College of Medicine, Seoul 02841, Republic of Korea. ³Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea. ⁴BK21 Graduate Program, Korea university College of Medicine, Seoul 02841, Republic of Korea. ⁵Department of Melanoma Medical Oncology and Immunology, U.T. MD Anderson Cancer Center, Houston, TX, USA. ⁶Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ⁷Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea. ⁸Department of Physiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea. ⁹NEX-I Inc., Seoul 05854, Republic of Korea.

^*Corresponding author.

Immunotherapy has emerged as a powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical application. Therefore, identifying immune-resistant factors, which can be targeted by clinically available drugs and it also can be a companion diagnostic marker, is needed to develop combination strategies. Here, using the transcriptome data of patients, and immune-refractory tumor models, we identify TCTP as an immune-resistance factor that correlates with clinical outcome of anti-PD-L1 therapy and confers immune-refractory phenotypes, decreased T cell trafficking to the tumor and resistance to cytotoxic T lymphocyte-mediated tumor cell killing. Mechanistically, TCTP activates the EGFR-AKT-MCL-1/CXCL10 pathway by phosphorylation-dependent interaction with Na, K ATPase. Furthermore, treatment with dihydroartenimsinin, the most effective agent impending the TCTP-mediated-refractoriness, synergizes with T cell-mediated therapy to control immune-refractory tumors. Thus, our findings suggest a role of TCTP in promoting immune-refractoriness, thereby encouraging a rationale for combination therapies to enhance the efficacy of T cell-mediated therapy.