Secreted phosphoprotein 1 (SPP1)

Overview

Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN), is a multifunctional, secreted glycoprotein that plays critical roles in immune regulation, cell adhesion, and extracellular matrix remodeling. As a phosphorylated protein containing integrin-binding and cell adhesion motifs, SPP1 serves as a key immunomodulatory factor in diverse pathophysiological contexts, including cancer, atherosclerosis, and inflammatory diseases. In the tumor microenvironment, SPP1 is predominantly expressed by tumor-associated macrophages (TAMs) and functions as a major driver of immunosuppression by promoting the infiltration and activation of regulatory T cells (Tregs) while simultaneously inhibiting CD8+ cytotoxic T cell function. Beyond its role as a soluble factor, SPP1 mediates cell-cell interactions and is regulated by multiple upstream signaling pathways including interferon signaling, STAT proteins, and receptor tyrosine kinase cascades, making it a focal point for understanding how tumors evade immune surveillance and develop resistance to immunotherapies.

SPP1 has emerged as a key molecular target in understanding tumor immune evasion mechanisms and therapy resistance. Recent studies have demonstrated that elevated SPP1 expression in macrophages and stromal compartments is strongly associated with poor prognosis and reduced response to checkpoint inhibitors and other anticancer therapies, highlighting its therapeutic potential as both a prognostic biomarker and intervention target.

Recent Publications Summary

Recent studies consistently implicate Secreted phosphoprotein 1 (SPP1, osteopontin) as a key mediator of therapy resistance and immunosuppressive remodeling in the tumor microenvironment. In breast cancer models, hypoxia-inducing anti-VEGF therapy triggered early epithelial SPP1 production, which recruited monocytes, promoted M2 macrophage polarization, and suppressed T cell cytotoxicity; pharmacological SPP1 depletion reduced hypoxia, decreased M2 infiltration, restored T cell activity, and enabled synergy between antiangiogenic therapy and anti-PD-L1 blockade 42454487Jul. A related commentary on renal cell carcinoma highlighted SPP1+ tumor-associated macrophages as important players in response to VEGFR kinase inhibitors and immunotherapy, with chronic treatment associated with metastatic spread 42442342Jul.

SPP1 was also linked to resistance to immune checkpoint blockade in hepatocellular carcinoma. In an anti-PD-1-resistant mouse model, FGFR1 upregulation activated MAPK signaling and induced SPP1 expression, which promoted macrophage infiltration and M2-type polarization while suppressing T cell recruitment and cytotoxic function; SPP1 knockdown or neutralization reduced macrophage accumulation and restored intratumoral T cell infiltration, and FGFR1 inhibition synergized with anti-PD-1 therapy 41786278Mar. In high-grade serous ovarian cancer, spatial profiling and single-cell analyses showed that sustained tumor cell-derived interferon induced SPP1 expression in tumor-associated macrophages via STAT signaling, generating immunosuppressive niches enriched in regulatory T cells and myofibroblastic cancer-associated fibroblasts; high baseline SPP1+ cells predicted poorer response to PARP inhibitor therapy and shorter progression-free survival, while SPP1 blockade restored PARP inhibitor sensitivity in HRD mouse models 41734034Feb.

Additional multi-omics studies extended these findings to other malignancies. In colorectal cancer, integrated single-cell and bulk analyses identified a CYP27A1-driven 26-hydroxycholesterol program that promoted immunosuppressive SPP1+APOE+ tumor-associated macrophages, associated with SPI1 activation, macrophage-Treg co-infiltration, and reduced CD8+ T cell infiltration 42399552Jul. In lung adenocarcinoma, SPP1 was included in a five-gene predictive model for platinum resistance, and spatial/multi-omics analyses were used to characterize tumor microenvironment dynamics associated with resistant subtypes 41662930Feb. Outside oncology, SPP1 was also used as a target in an osteopontin-based biosensing platform for monitoring bone-health biomarkers 42108056May, and in atherosclerosis research, osteopontin-targeted nanoparticles were used to selectively accumulate in foam cells for ultrasound-guided sonodynamic therapy 42117484May.

What Changes, What Holds

1. SPP1 now looks like a therapy-induced resistance node that can be therapeutically intercepted
NEW DIRECTION Anti-VEGF treatment is not just associated with SPP1-rich immunosuppression; it appears to induce an early epithelial SPP1 program that helps drive monocyte recruitment, M2 polarization, and T cell suppression, with SPP1 depletion restoring sensitivity to combined antiangiogenic and anti-PD-L1 therapy 42454487Jul. The renal cell carcinoma commentary points in the same direction, suggesting SPP1+ macrophages may help shape outcomes under VEGFR inhibition and immunotherapy 42442342Jul. This extends the baseline from a general resistance biomarker to a treatment-emergent mediator.

2. Upstream signaling can place SPP1 at the center of checkpoint and PARP inhibitor resistance
REINFORCES These studies sharpen the baseline claim that SPP1 is a major driver of immune evasion by showing concrete upstream routes into its expression and downstream effects on macrophage and T cell behavior 41786278Mar41734034Feb. They do not overturn the established macrophage/TAM-centered model; instead, they strengthen it by linking SPP1 to specific resistance states and by showing that blocking SPP1 can restore drug sensitivity in preclinical settings. The unresolved issue is how broadly these pathways generalize across tumors and treatment contexts.

3. SPP1 is emerging as a broader marker of immunosuppressive macrophage states across Cancers, not just a macrophage product in the tumor microenvironment
NEW DIRECTION Colorectal and lung adenocarcinoma analyses extend the baseline beyond the already established TAM immunosuppression story by tying SPP1 to defined resistant subtypes, co-infiltrating Treg-rich niches, and predictive modeling for platinum response 42399552Jul41662930Feb. The atherosclerosis and biosensing examples are outside the tumor setting entirely, so they do not alter the cancer-focused baseline but do show that SPP1 is being repurposed as a measurable or targetable molecule in other fields 42108056May42117484May.

Overview update candidates: treatment-induced SPP1 as a resistance mediator; upstream FGFR1/MAPK and interferon/STAT control of SPP1-linked resistance; broader cross-cancer and non-oncology uses of SPP1 as a biomarker/target.