Research progress of SPP1 in cancer regulation: Tumorigenesis, metastasis, tumor microenvironment, immunity and therapeutic targets (Review).

Abstract

Secreted phosphoprotein 1 (SPP1, also known as osteopontin, OPN) is a multifunctional matricellular glycoprotein that is aberrantly overexpressed in nearly all major human malignancies. It functions as a central signaling hub that drives tumor initiation, sustains cancer stemness, accelerates invasion and metastasis, remodels the tumor microenvironment (TME), and mediates immune evasion. SPP1 exerts its oncogenic effects by binding to integrin family receptors (αvβ3, αvβ5, α5β1) and CD44 variants, thereby activating canonical oncogenic signaling cascades including PI3K/AKT, NF‑κB, MAPK/ERK and Wnt/β‑catenin. Beyond cancer‑cell‑autonomous functions, SPP1 orchestrates a complex immunosuppressive TME by modulating tumor‑associated macrophages, cancer‑associated fibroblasts, myeloid‑derived suppressor cells, regulatory T cells (Tregs) and cytotoxic T‑cell activity. Preclinical studies have validated SPP1 as a promising therapeutic target, with strategies including neutralizing antibodies, RNA aptamers, small‑molecule inhibitors, RNA interference and combination immunotherapy showing potent antitumor efficacy. The present review systematically summarizes the molecular basis of SPP1, its receptor‑mediated signaling, multifaceted regulatory roles in tumor biology, TME remodeling, immune suppression and advances in SPP1‑targeted therapy. Current challenges, emerging concepts and future directions to translate SPP1‑targeted interventions into clinical practice for cancers were further discussed.