CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
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Research Article Cell biology Oncology

CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models

Abstract

Inactivation of cyclin-dependent kinase 12 (CDK12) defines an immunogenic molecular subtype of prostate cancer characterized by genomic instability and increased intratumoral T cell infiltration. This study revealed that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis showed that reduced CDK12/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12/13 depletion or targeted degradation induced cytosolic nucleic acid release, triggering STING pathway activation. CDK12/13 degradation delayed tumor growth and synergized with anti–PD-1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8+ T cell infiltration and activation within tumors. Notably, the antitumor effects of this combination required STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12-mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate antitumor immunity and potentiate responses to immunotherapies.

Authors

Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan

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Figure 5

Antitumor activity of CDK12/13 degradation is STING dependent.

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Antitumor activity of CDK12/13 degradation is STING dependent. (A) Enric...
(A) Enrichment of the indicated pathways in Myc-CaP subcutaneous (s.c.) tumors from FVB mice treated with YJ1206 compared to vehicle control. Adj., adjusted. (B) All pathways significantly enriched by GSEA, utilizing the MSigDB Hallmark database, in Myc-CaP s.c. tumors from FVB mice treated with YJ1206 compared to vehicle control. Type I and II IFN responses are highlighted in red. Adj., adjusted. (C and D) Representative images (C) or quantification (D) of immunofluorescence (for p-STING and MHC-I) or immunohistochemistry (for p-IRF3) performed on Myc-CaP tumor tissues from mice treated with vehicle, anti–PD-1 (α-PD-1), YJ1206, or the combination (combo) of α-PD-1 and YJ1206 (n = 4 mice per group). Scale bar: 40 μm. (E) Left: Growth curves of s.c. tumors derived from CT26 cells with or without Sting1 KO, in BALB/c mice treated with the combination (combo) of α-PD-1 and YJ1206. Right: Growth curves of s.c. tumors derived from CT26 cells with Sting1 KO, in Sting1-KO BALB/c mice treated with the combination (combo) of α-PD-1 and YJ1206. YJ1206 was administered orally at a dose of 25 mg/kg, 3 times per week, and α-PD-1 was administered intraperitoneally at a dose of 100 μg/mouse every 3 days (n = 5 mice per group). Data are displayed as mean ± SEM. Significance in D was determined by 2-tailed t test and by 2-way ANOVA in E. Bonferroni’s correction was applied for multiple comparisons in D and E.