Reprogramming the tumor immune landscape through SPP1 targeting

Abstract Beyond its canonical roles in bone mineralization and extracellular matrix remodeling, secreted phosphoprotein 1 (SPP1) has emerged as a central regulator of the tumor microenvironment (TME), orchestrating immunosuppressive programs that drive immune evasion and tumor progression. Produced by tumor cells, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts, SPP1 signals through integrins and CD44 variants to promote pro-tumor macrophage polarization, impair innate immune cell function, induce T cell exclusion and exhaustion, and remodel the extracellular matrix to reinforce immune exclusion. Growing evidence has identified the SPP1 axis as a promising therapeutic target, leading to the development of strategies including SPP1 neutralization, receptor blockade, depletion or reprogramming of SPP1⁺ TAMs, and combination therapies with immune checkpoint inhibitors, STING agonists, cytokine-based therapies, radiotherapy, and chemotherapy. This review summarizes the molecular and cellular mechanisms by which SPP1 shapes the tumor immune landscape, highlights emerging therapeutic approaches targeting the SPP1 axis, and discusses key translational challenges, including the context-dependent nature of SPP1 signaling, biomarker development, and patient stratification. Targeting the SPP1 axis offers a promising strategy for remodeling the TME and enhancing antitumor immunity.