On January 15, the research team led by Academician Zhang Zemin at Chongqing Medical University, together with collaborators, published a paper in Cancer Cell titled Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity. Using a novel parallel strategy of “computational prediction + functional screening,” the study successfully identified ADAM12 as a key target that can reprogram cancer-associated fibroblasts (CAFs) and help overcome resistance to immunotherapy.
A key challenge in cancer immunotherapy is that “cold tumors” are not responsive to treatment, which is closely associated with the tumor microenvironment being rich in myofibroblast-like CAFs that have immunosuppressive functions. However, CAFs are highly heterogeneous and exhibit strong state plasticity. The precise reprogramming of them from a tumor-promoting state into a tumor-suppressing state has long remained an unresolved problem in the field.
This study integrates computational biology with high-throughput functional screening to investigate therapeutic targets in fibroblasts. The team first identified 54 potential key genes through computational screening by integrating multi-omics clinical data. In parallel, they established a patient-derived fibroblast cell bank and used CRISPRi/a Perturb-seq for functional screening, systematically mapping—for the first time—a genotype–phenotype causal regulatory network in patient-derived CAFs. The study found that the type I interferon response program and the myofibroblast activation program exist in a key antagonistic relationship, and that ADAM12 serves as a central hub regulating this balance. Targeting ADAM12 can effectively activate the anti-tumor interferon response in CAFs and remodel the tumor microenvironment. Experimental results demonstrated that this strategy significantly inhibited tumor growth in multiple mouse models and enhanced CD8+ T-cell infiltration and function. When combined with PD-L1 blockade therapy, it showed synergistic effects in drug-resistant models.
This study established a complete framework ranging from target discovery to mechanistic validation, revealing an actionable reprogramming pathway for CAFs. It identified ADAM12 as a novel therapeutic target that is minimally expressed in normal tissues and combines high efficacy with potential safety, providing a new strategy and hope for overcoming resistance to immunotherapy, particularly in reshaping the “cold tumor” microenvironment.
Original article：https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00552-5
（Translated by AI）
