Research Insight - The Team Led by Academician Zemin Zhang at Chongqing Medical University Identifies a Novel Immunotherapy Target via Single-Cell Screening

Recently, Academician Zemin Zhang from Chongqing Medical University, Associate Researcher Dongfang Wang from Peking University, and Professor Jianzhong Xi from Peking University, among others, published a research article entitled “Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity” in Cancer Cell (Q1, IF = 47.2). This study identified ADAM12 as a fibroblast checkpoint through single-cell screening. Loss of ADAM12 was found to delay tumor progression and enhance tumor sensitivity to immunotherapy, thereby providing a novel therapeutic target for cancer immunotherapy.

A central challenge in tumor immunotherapy is the limited responsiveness of tumors to treatment, which is closely associated with the abundance of immunosuppressive cancer-associated fibroblasts (CAFs) within the tumor microenvironment. However, CAFs exhibit high heterogeneity and remarkable phenotypic plasticity. How to precisely reprogram CAFs from a tumor-promoting state to a tumor-suppressive state remains an unresolved issue in the field.

In this study, computational biology was integrated with high-throughput functional screening to investigate fibroblast targets. The research team first performed integrative analysis of multi-omics clinical datasets to computationally identify 54 candidate key genes. Meanwhile, a patient-derived fibroblast library was established, and CRISPRi/a Perturb-seq technology was employed for functional screening. For the first time, a genotype–phenotype causal regulatory network was systematically mapped in patient-derived CAFs. The study revealed a critical antagonistic relationship between the type I interferon response program and the myofibroblast activation program, with ADAM12 serving as a central regulatory hub of this balance. Targeting ADAM12 effectively activates the antitumor interferon response in CAFs and remodels the tumor microenvironment. Experimental results demonstrated that this strategy significantly inhibited tumor growth and enhanced CD8⁺ T cell infiltration and function across multiple mouse models. Moreover, when combined with PD-L1 blockade therapy, it exhibited synergistic therapeutic effects in resistant models.

This study establishes a comprehensive paradigm from target discovery to mechanistic validation, revealing an actionable reprogramming pathway for CAFs. It identifies ADAM12 as a novel therapeutic target characterized by minimal expression in normal tissues, along with high efficacy and potential safety. These findings provide a new strategy and promising avenue for overcoming resistance to immunotherapy, particularly for transforming “cold” tumor microenvironments.

Fifteen days after implantation of orthotopic Lewis lung carcinoma, mice were intraperitoneally injected with luciferin substrate. Ten minutes later, the mice were euthanized, and the lungs were excised for ex vivo tumor burden quantification using the AniView multimodal in vivo imaging system (Guangzhou Biolight Biotechnology Co., Ltd.).

Article link:

https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00552-5