On January 15, 2026, the team led by Professor Zemin Zhang from the Biomedical Pioneering Innovation Center (BIOPIC) at Peking University / Chongqing Medical University, together with Professor Jianzhong Xi from the College of Future Technology at Peking University and their collaborators, published a research article entitled Single-cell screens identify ADAM12 as a fibroblast checkpoint impeding anti-tumor immunity in Cancer Cell. Using a parallel strategy that combined computational prediction with functional screening, the study identified ADAM12 as a key regulator of CAF state transitions and a potential therapeutic target for remodeling the tumor microenvironment.

Figure 1. Research strategy and key findings

Cancer immunotherapy has reshaped modern cancer treatment, yet therapeutic resistance remains a major clinical challenge. Many resistant tumors are enriched with cancer-associated fibroblasts (CAFs), particularly myofibroblast-like CAFs, which can impair immune activity and limit immune infiltration. Although fibroblast targeting has long been viewed as a promising way to convert immunologically “cold” tumors into “hot” ones, progress has been hindered by the remarkable heterogeneity and plasticity of CAFs. Understanding how to reprogram CAFs from an immunosuppressive state to an anti-tumor state therefore remains a central question in the field.

To address this gap, the researchers established a library of patient-derived fibroblasts and performed both gain-of-function and loss-of-function CRISPRi/a Perturb-seq screens, enabling causal genotype-to-phenotype analysis in human cancer fibroblasts. By integrating large-scale human cancer single-cell RNA sequencing data with GTEx and TCGA datasets, the team prioritized candidate genes and then systematically evaluated their functions in patient-derived fibroblasts.

The researchers identified nine core transcriptional modules corresponding to fibroblast states observed in tumors by comparing in vivo and in vitro single-cell transcriptomic profiles. Further analyses showed that the type I interferon response program strongly antagonizes the myofibroblast-like program, with ADAM12 emerging as a central node that helps govern this balance through bidirectional regulation of TGFβ and type I interferon signaling.

Fibroblast-specific ADAM12 targeting shows potent anti-tumor activity across multiple preclinical models, including melanoma (B16), colorectal cancer (MC38), pancreatic cancer (KPC), and lung cancer (LLC). ADAM12 targeting reprogrammed fibroblasts toward an anti-tumor state by activating tumor-suppressive interferon responses while reducing pro-tumor myofibroblast features. Loss of ADAM12 reshaped the tumor microenvironment by loosening the extracellular matrix, normalizing vasculature, and enhancing CD8+ T-cell infiltration and function, particularly in immunologically “cold” tumors. Importantly, ADAM12 targeting also improved the efficacy of PD-L1 blockade in resistant tumor models, highlighting its promise in combination therapy.

The study’s co-corresponding authors are Professor Zemin Zhang (BIOPIC, Peking University / Chongqing Medical University); Associate Researcher Dongfang Wang (BIOPIC, Peking University); Professor Jianzhong Xi (the College of Future Technology, Peking University); and Dr. Jianan Li (Changping Laboratory; now Researcher at the Beijing-Tianjin-Hebei Biomedical Frontiers Innovation Center, Peking University). Co-first authors are Dr. Jianan Li, Huilan Liu (the School of Life Sciences, Peking University), Qile Guo (the School of Life Sciences, Tsinghua University), and Yiying Zhang (the Academy for Advanced Interdisciplinary Studies, Peking University). The work also received important support from Associate Researcher Linnan Zhu (BIOPIC, Peking University), Director Jirun Peng (Beijing Shijitan Hospital), and Researcher Xueda Hu (Beijing-Tianjin-Hebei Biomedical Frontiers Innovation Center, Peking University).

Paper link: https://doi.org/10.1016/j.ccell.2025.12.018