Periostin promotes sarcoma growth by increasing tumor associated macrophages. [CITE-Seq]

Soft tissue sarcomas (STS) are characterized by abundant extracellular matrix (ECM) deposition, yet the functional contribution of specific ECM components remains poorly understood. Here, 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 Postn in vivo reduced tumor growth without altering tumor cell proliferation or intrinsic signaling pathways, suggesting a non-cell-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 (TAMs). Single-cell RNA sequencing revealed that Postn silencing reprograms the myeloid compartment, increasing interferon-responsive and pro-inflammatory 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.