Syndecan-3 couples tumor mechanics to immunosuppressive macrophage identity

Tumor-associated macrophages adopt suppressive states, but how tumor stress installs these programs remains unclear. Here, we identify syndecan-3 (SDC3) as a macrophage-intrinsic mechanosensory regulator by integrating in vivo functional screening, single-cell and spatial profiling, and genetic and pharmacological perturbation. SDC3+ macrophages accumulate in hypoxic, stiff tumor niches and suppress antitumor cytotoxic T-cell responses. Matrix stiffness increases mechanical loading on SDC3, reorganizes an SDC3-associated scaffold and opens suppressive chromatin loci. This program engages a CDK7–MAFB relay to induce TREM2, which functions as a required suppressive effector in mice. Human-cell assays support a species-specific TREM2-associated inhibition mechanism. Naldemedine engages TREM2, restores cytotoxic T-cell activity, improves tumor control and enhances immune-checkpoint blockade in vivo. These findings define a targetable SDC3–CDK7–MAFB–TREM2 axis linking hypoxia and tissue mechanics to macrophage-mediated immune evasion. Tumor associated macrophages (TAMs) are a main component of the immunosuppressive tumor microenvironment (TME). Here the authors identify syndecan-3 as a macrophage-intrinsic mechano-sensor that drives immunosuppression in the TME.