癌关联成纤维细胞（CAFs）是免疫抑制细胞的理论在过去的十年中盛行。然而，最近的高通量、高分辨率基于间充质的单细胞研究利用计算进展来进行功能特征化，突显了免疫刺激CAF的存在。我们的团队和其他人已经揭示和实验证实了癌抗原呈递CAF在体内外的T细胞免疫中的关键功能，推翻了CAFs阻碍肿瘤适应性免疫排斥的传统假设。在这篇综述中，我将肿瘤的滤泡和非滤泡、非内皮基质统一为“外周适应性免疫间充质”框架，并将一些CAFs亚型定位为直接的正调节剂。基于CAFs对癌抗原呈递和第二触觉学说的理解，后者假设完整的T细胞极化需要与抗原呈递细胞在抗原所在的非淋巴组织中相互作用，我重新设计了“癌症免疫周期”，将肿瘤内部癌特异性CD4+T细胞的激活纳入其中。最后，提出了一份利用免疫刺激CAF状态的治疗路线图。©2023. Springer Nature 有限公司。

The theory that cancer-associated fibroblasts (CAFs) are immunosuppressive cells has prevailed throughout the past decade. However, recent high-throughput, high-resolution mesenchyme-directed single-cell studies have harnessed computational advances to functionally characterize cell states, highlighting the existence of immunostimulatory CAFs. Our group and others have uncovered and experimentally substantiated key functions of cancer antigen-presenting CAFs in T cell immunity, both in vitro and in vivo, refuting the conventional assumption that CAFs impede adaptive immune rejection of tumours. In this Perspective, I unify the follicular and non-follicular, non-endothelial stroma of tumours under the 'peripheral adaptive immune mesenchyme' framework and position subsets of CAFs as direct positive regulators of the adaptive immune system. Building on the understanding of cancer antigen presentation by CAFs and the second touch hypothesis, which postulates that full T cell polarization requires interaction with antigen-presenting cells in the non-lymphoid tissue where the antigen resides, I re-design the 'cancer-immunity cycle' to incorporate intratumoural activation of cancer-specific CD4+ T cells. Lastly, a road map to therapeutic harnessing of immunostimulatory CAF states is proposed.© 2023. Springer Nature Limited.