Core Insights - The article discusses the challenges in clinical trials targeting cancer-associated fibroblasts (CAFs), which are crucial tumor-promoting factors, due to their inherent functional plasticity and the opaque regulatory circuits behind their heterogeneous phenotypes [2] Group 1: Research Findings - A study published in Cancer Cell identified ADAM12 as a fibroblast checkpoint that impedes anti-tumor immunity, with its deletion delaying tumor progression and making tumors more sensitive to immunotherapy [3] - The research team developed a systematic screening method based on complementary CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) to screen patient-derived fibroblasts [5] - The study found that the I-type interferon (IFN-I) response program is a primary antagonistic axis against TGF-β-driven tumor-promoting myofibroblast activation, with ADAM12 mediating this relationship [5] Group 2: Implications for Treatment - Deletion of ADAM12 triggers the IFN-I response program, reconfiguring the myofibroblast population into progenitor-like states, revitalizing T-cell-based immune responses, and inducing tumor rejection in various mouse models [5] - The research positions ADAM12 as a potential target for therapeutic interventions, paving the way for future treatment strategies [5][7] - The study emphasizes the conversion of TGF-β dependent myCAF programs into IFN-I response states to exert anti-tumor activity, enhancing T-cell infiltration and sensitivity to immunotherapy [7]