From TLS architecture to functional immune niches: division of labor among CAFs, HEVs, and antigen-presenting cells in cancer immunotherapy

Abstract

Tertiary lymphoid structures (TLSs) are associated with antitumor immunity and have prompted efforts to induce lymphoid organization within tumors. The central interpretive problem is whether the resulting tissue changes contribute to treatment benefit or accompany effects mediated by other cells. Building on established TLS biology, this Review compares the cellular targets, functional measurements, and antitumor outcomes of stromal, endothelial, and antigen-presenting-cell interventions, with particular attention to cancer-associated fibroblasts (CAFs). Across experimental systems, defined CAF states support chemokine production and lymphocyte recruitment, whereas vascular entry and antigen-dependent T-cell responses are demonstrated through distinct interventions. The synthesis distinguishes a stromal contribution to immune organization from evidence that this contribution is required for tumor control, preserving the model and anatomical setting in which each relationship was tested. Mechanistic support comes mainly from murine and engineered systems, while human studies chiefly establish spatial relationships and clinical associations. For therapies that remodel TLS-associated niches, this comparison identifies the induced functions whose contribution to treatment benefit needs to be tested before tissue changes are used to guide clinical treatment.