TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages

Transforming growth factor β (TGF-β) signaling in the tumor microenvironment predicts resistance to immune checkpoint blockade (ICB). While TGF-β inhibition enhances ICB efficacy in murine cancer models, clinical trials have yet to demonstrate benefit, underscoring the need to better understand its immunoregulatory roles across disease contexts. Using mouse models of advanced colorectal cancer and patient-derived data, we demonstrate that TGF-β impairs antitumor immunity at multiple levels in liver metastases. It acts directly on T cells to block recruitment of peripheral memory CD8+ T cells, thereby limiting the effectiveness of ICB. Concurrently, TGF-β instructs tumor-associated macrophages to suppress clonal expansion of newly arrived T cells by inducing SPP1 expression. This extracellular matrix protein promotes collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, ultimately driving ICB resistance. Our findings reveal how TGF-β coordinates immunosuppressive mechanisms across innate and adaptive immune compartments to promote metastasis, offering new avenues to improve immunotherapy in colorectal cancer. Targeting TGFBR1 in transplantable mouse colorectal tumor organoids improves response to anti-PD-L1 therapy. Mechanistically, TGF-β abrogates clonal expansion of T effector and memory phenotypes and indirectly inhibits T cell activity by regulating immunosuppressive tumor-associated macrophage activity.