Targeting tumor-intrinsic STK40 induces immune vulnerability and drives T cell reinvigoration
(1) Zhu L (2) Zhang S (3) Li B (4) Liu X (5) Yang C (6) Tang X (7) Chai J (8) Yang X (9) Yu C (10) Liao H (11) Cao Z (12) Liao L (13) Wang W (14) Yuan S (15) Gao Q (16) Sun C (17) Bernards R (18) Yang Y (19) Qin W (20) Wang C
Using in vivo CRISPR screens, Zhu et al. identified serine/threonine kinase 40 (STK40) as a novel regulator of immune evasion in hepatocellular carcinoma (HCC). Stk40 loss disrupted COP1-mediated IFNGR1 degradation, stabilized IFNGR1, restored tumor-intrinsic IFNγ signaling, and sensitized HCC cells to CD8+ T cell-mediated killing. Stk40 deficiency simultaneously induced tumor-derived GM-CSF, enhancing cDC1 infiltration, antigen cross-presentation, and CD8+ T cell activation. LNP-siRNA-mediated STK40 targeting synergized with PD-1 blockade in suppressing tumor growth in multiple cancer models.
Contributed by Shishir Pant
(1) Zhu L (2) Zhang S (3) Li B (4) Liu X (5) Yang C (6) Tang X (7) Chai J (8) Yang X (9) Yu C (10) Liao H (11) Cao Z (12) Liao L (13) Wang W (14) Yuan S (15) Gao Q (16) Sun C (17) Bernards R (18) Yang Y (19) Qin W (20) Wang C
Using in vivo CRISPR screens, Zhu et al. identified serine/threonine kinase 40 (STK40) as a novel regulator of immune evasion in hepatocellular carcinoma (HCC). Stk40 loss disrupted COP1-mediated IFNGR1 degradation, stabilized IFNGR1, restored tumor-intrinsic IFNγ signaling, and sensitized HCC cells to CD8+ T cell-mediated killing. Stk40 deficiency simultaneously induced tumor-derived GM-CSF, enhancing cDC1 infiltration, antigen cross-presentation, and CD8+ T cell activation. LNP-siRNA-mediated STK40 targeting synergized with PD-1 blockade in suppressing tumor growth in multiple cancer models.
Contributed by Shishir Pant
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.
Author Info:
(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. (3) 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. (4) Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (5) 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. (6) 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. (7) 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. (8) Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. (9) 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. (10) Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (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. (12) 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. (13) 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. (14) The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China. (15) Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. (16) German Cancer Research Center, Division Immune Regulation in Cancer, Heidelberg, Germany. (17) 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: r.bernards@nki.nl. (18) Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: yuyang@shsmu.edu.cn. (19) 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: wxqin@sjtu.edu.cn. (20) 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: cwang@shsci.org.
