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.
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