Periostin Promotes Sarcoma Growth by Promoting Tumor-Associated Macrophage Migration and Differentiation.

Soft-tissue sarcomas (STS) are characterized by abundant extracellular matrix (ECM) deposition, yet the functional contribution of specific ECM components remains poorly understood. In this study, we identify periostin (POSTN), a matricellular protein, as a regulator of sarcoma progression and the tumor immune microenvironment. Analysis of human sarcoma datasets revealed that high POSTN expression correlates with poor prognosis and elevated expression of ECM-related and myeloid cell-associated genes. In murine genetic models of sarcoma, tumors expressing high levels of Postn displayed enhanced expression of ECM genes and monocyte-recruiting cytokines. Functional silencing of Postnin vivo reduced tumor growth without altering tumor cell proliferation or intrinsic signaling pathways, suggesting a noncell-autonomous mechanism. Instead, Postn-deficient tumors showed increased infiltration of CD4+ and CD8+ T cells and reduced proportions of immunosuppressive myeloid cells, including tumor-associated macrophages (TAM). Single-cell RNA sequencing revealed that Postn silencing reprograms the myeloid compartment, increasing IFN-responsive and proinflammatory subsets. Mechanistically, recombinant POSTN promoted monocyte migration and maturation into macrophages in vitro, supporting its role as a chemoattractant and differentiation cue. Therapeutic neutralization of POSTN partially recapitulated the immunologic remodeling but was insufficient to reduce tumor burden as monotherapy. SIGNIFICANCE: Our findings position POSTN as a key stromal regulator in STS, linking tumor-derived ECM components to immune evasion via myeloid cell recruitment and education. These results open avenues for targeting POSTN as an adjuvant strategy to enhance the efficacy of immunotherapies and overcome the immune-excluded phenotype of sarcoma.