Targeting tumor-intrinsic STK40 induces immune vulnerability and drives T cell reinvigoration PMID: 42208540

ADC Targets in Oncology

2026-04-10

Targeting tumor-intrinsic STK40 induces immune vulnerability and drives T cell reinvigoration

Cancer Cell. 2026 Jul 13;44(7):1496-1508.e10. doi: 10.1016/j.ccell.2026.05.001.

Lili Zhu ¹ , Sisi Zhang ¹ , Botai Li ² , Xueliang Liu ³ , Chen Yang ¹ , Xiangyu Tang ¹ , Jiayi Chai ¹ , Xupeng Yang ⁴ , Chune Yu ¹ , Huiping Liao ⁵ , Zhirui Cao ¹ , Long Liao ¹ , Wei Wang ¹ , Shengxian Yuan ⁶ , Qiang Gao ⁴ , Chong Sun ⁷ , René Bernards ⁸ , Yu Yang ⁹ , Wenxin Qin ¹⁰ , Cun Wang ¹¹

Affiliations

1. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3. Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4. Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
5. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6. The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
7. German Cancer Research Center, Division Immune Regulation in Cancer, Heidelberg, Germany.
8. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: [email protected].
9. Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
10. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
11. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute & Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].

Abstract

Immunotherapy has revolutionized Cancer treatment, yet its efficacy in hepatocellular carcinoma (HCC) remains limited and the mechanisms of resistance are poorly defined. Using in vivo CRISPR-Cas9 screens, we identify serine/threonine kinase 40 (STK40) as a previously unrecognized regulator of immune evasion. Stk40 ablation synergizes with PD-1 blockade to induce tumor regression. Hepatocyte-specific Stk40 deletion abolishes tumorigenesis in hydrodynamic plasmid-driven HCC models. Mechanistically, STK40 scaffolds the COP1 ubiquitin Ligase to promote interferon gamma receptor 1 (IFNGR1) degradation. Genetic depletion of Stk40 stabilizes IFNGR1, restoring tumor cell sensitivity to T cell cytotoxicity. Concurrently, Stk40 loss triggers autonomous GM-CSF secretion, enhancing the infiltration and activation of conventional type 1 dendritic cells, which promotes antigen cross-presentation and CD8⁺ T cell activation. Pharmacological inhibition of STK40 using LNP-siRNA, combined with PD-1 blockade, elicits potent anti-tumor responses across multiple Cancer types. These findings establish STK40 as a dual-action therapeutic target to overcome resistance to anti-tumor immunity.

Keywords

CRISPR screening; STK40; anti-tumor immunity; hepatocellular carcinoma; immunotherapy.