Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity PMID: 41544628

ADC Targets in Oncology

2026-04-10

Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity

Cancer Cell. 2026 Feb 9;44(2):424-442.e14. doi: 10.1016/j.ccell.2025.12.018.

Jianan Li ¹ , Huilan Liu ² , Qile Guo ³ , Yiying Zhang ² , Jiaxin Li ⁴ , Tian Diao ² , Liangtao Zheng ⁵ , Zenghua Deng ⁶ , Yu Yang ⁷ , Xueyan Chen ² , Shishang Qin ² , Jinhu Li ² , Yao He ² , Wanzhuo He ² , Dongfang Liu ⁶ , Yufei Bo ² , Chang Liu ² , Huinan Lu ⁸ , Hongtao Fan ² , Xueda Hu ⁹ , Jirun Peng ¹⁰ , Linnan Zhu ² , Jianzhong Jeff Xi ¹¹ , Dongfang Wang ¹² , Zemin Zhang ¹³

Affiliations

1. Changping Laboratory, Beijing 102206, China; Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Peking University, Beijing 100871, China; Peking University Beijing-Tianjin-Hebei Biomedical Pioneering Innovation Center, Tianjin 300405, China. Electronic address: [email protected].
2. Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Peking University, Beijing 100871, China.
3. Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Peking University, Beijing 100871, China; Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
4. State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China.
5. Analytical Biosciences Limited, Beijing 100084, China.
6. Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
7. Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Peking University, Beijing 100871, China; Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China.
8. GeneX Health Co, Led, Beijing 100195, China.
9. Analytical Biosciences Limited, Beijing 100084, China; Peking University Beijing-Tianjin-Hebei Biomedical Pioneering Innovation Center, Tianjin 300405, China.
10. Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; Ninth School of Clinical Medicine, Peking University, Beijing 100038, China.
11. State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China. Electronic address: [email protected].
12. Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Peking University, Beijing 100871, China. Electronic address: [email protected].
13. Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Peking University, Beijing 100871, China; Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].

Abstract

Clinical trials targeting cancer-associated fibroblasts (CAFs)-crucial pro-tumoral factors in cancer-have almost all failed. This may be ascribed to their intrinsic functional plasticity and the opaque regulatory circuits underlying their heterogeneous phenotypes within tumors. We address these by developing a systematic screening approach for patient-derived fibroblasts using complementary CRISPR interference (CRISPRi) and activation (CRISPRa)-based Perturb-seq. An anti-tumoral interferon (IFN)-I response-associated program is identified as the primary antagonism axis counteracting TGF-β-driven pro-tumoral myofibroblast activation. ADAM12 emerges as a molecular checkpoint mediating this relationship. Its ablation elicits IFN-I-responsive programs, reconfigures myofibroblast population structures into progenitor-like states, revitalizes T cell-based immune responses, and induces tumor rejection across various murine models. Further combined with human genomics data analysis, our findings position ADAM12 as a potential target for fibroblasts, paving the way for actionable therapeutic interventions.

Keywords

CAFs; CRISPRa; CRISPRi; Perturb-seq; anti-tumoral fibroblasts; cancer-associated fibroblasts; immunotherapy; myofibroblast activation; patient-derived organoid-fibroblast co-culture; turning cold tumors hot.