SPP1 is a secreted glycosylated phosphoprotein with a long-established resume in skeletal biology, where it participates in bone mineralization and the remodeling of the extracellular matrix. But in tumors, the same molecule takes on a darker role. The review synthesizes evidence showing that SPP1 is produced by multiple players within the tumor microenvironment, including tumor cells themselves, tumor-associated macrophages and cancer-associated fibroblasts. Once secreted, it signals through a family of cell-surface receptors, chiefly integrins that recognize its arginine-glycine-aspartic acid motif, as well as variants of the CD44 receptor. Through these interactions, SPP1 transmits instructions that reshape how immune cells behave, how they move through tissue, and whether they can reach the tumor at all.

One of the most consequential effects of SPP1 signaling is its influence on macrophages, the versatile immune cells that populate nearly every tumor. The review describes how SPP1 drives the polarization of tumor-associated macrophages toward a pro-tumor phenotype, a state in which these cells abandon their immune-surveillance duties and instead support tumor growth, angiogenesis and tissue remodeling. Single-cell RNA sequencing studies, which allow researchers to profile gene expression in individual cells, have repeatedly identified distinct populations of SPP1-positive macrophages in human tumors, and these cells are consistently associated with poor clinical outcomes. Rather than simply being bystanders, these macrophages appear to be active architects of an immunosuppressive environment, secreting SPP1 that reinforces their own suppressive identity and that of their neighbors.

The consequences extend well beyond macrophages. According to the review, SPP1 impairs the function of innate immune cells, the rapid-response arm of the immune system that includes natural killer cells and dendritic cells. It also induces the exclusion and exhaustion of T cells, the cytotoxic lymphocytes that immunotherapies such as immune checkpoint inhibitors are designed to unleash. T cell exhaustion is a state of progressive dysfunction in which T cells lose their ability to kill tumor cells, and SPP1 appears to promote this process while simultaneously building physical barriers that keep T cells away from tumor cells in the first place. By remodeling the extracellular matrix, the fibrous scaffold that permeates tumors, SPP1 helps create a form of immune exclusion in which anti-tumor lymphocytes linger at the tumor margin, unable to penetrate the tumor core.

This combination of effects helps explain why many patients fail to respond to immune checkpoint inhibitors, the blockbuster therapies that block inhibitory receptors such as PD-1 and have transformed the treatment of melanoma, lung cancer and other malignancies. Checkpoint inhibitors work best in tumors that are already infiltrated by T cells, so-called hot tumors. SPP1-rich tumors, by contrast, tend to be cold, lacking meaningful lymphocyte infiltration and exhibiting dense, suppressive stroma. The review positions the SPP1 axis as a promising therapeutic target precisely because it operates upstream of these failures: neutralizing SPP1 or blocking its receptors could convert a cold, excluded tumor into one that immune therapies can actually reach.

Encouragingly, the review catalogs a growing arsenal of strategies aimed at doing exactly that. Direct SPP1 neutralization, using antibodies or other decoy molecules, aims to mop up the protein before it reaches its receptors. Receptor blockade seeks to sever the downstream signaling that integrins and CD44 variants transmit into immune and stromal cells. A third approach targets the source: depleting or reprogramming the SPP1-positive tumor-associated macrophages that manufacture much of the tumor’s supply. Each strategy attacks a different node of the axis, and the review suggests that combining them with existing modalities may be where the greatest potential lies.

Those combination possibilities are particularly striking. The authors describe evidence supporting the pairing of SPP1 targeting with immune checkpoint inhibitors, with agonists of the STING pathway, a innate immune sensor that when activated can ignite anti-tumor inflammation, with cytokine-based therapies, and with conventional treatments such as radiotherapy and chemotherapy. The logic is complementary: SPP1 blockade dismantles the immunosuppressive and exclusionary architecture of the tumor, while the partner therapy supplies or amplifies the immune attack. Radiotherapy and chemotherapy, for their part, can release tumor antigens and induce immunogenic cell death, effects that SPP1 targeting may help convert into durable systemic immunity rather than transient local responses.

Drug delivery innovation is also entering the picture. The review highlights work on lipid nanoparticles, the same lipid-based vehicles that proved their worth in mRNA vaccines, engineered to deliver SPP1-targeting small interfering RNA into tumors. One described design uses mannosylated nanoparticles, decorated with sugar molecules that guide them toward macrophages, to deliver SPP1 siRNA in combination with interferon-gamma, a cytokine that can push macrophages back toward an anti-tumor state. Such approaches illustrate how the field is moving beyond simple antibody blockade toward precision tools that can reprogram specific cell populations within the tumor microenvironment, potentially resetting the balance between suppression and immunity at its source.

Yet the review is careful to temper enthusiasm with a sober accounting of the translational challenges ahead. SPP1 signaling is context-dependent: the same molecule can exert different, sometimes opposing, effects depending on the receptor engaged, the cell type targeted and the stage of tumor progression. Osteopontin has documented roles in normal wound healing and tissue homeostasis, raising the possibility that systemic blockade could interfere with beneficial biology. The authors also emphasize the need for biomarker development and patient stratification, since identifying which patients harbor SPP1-driven, immune-excluded tumors will be essential for selecting who benefits from SPP1-directed therapies and for designing clinical trials capable of demonstrating meaningful benefit.

The broader message of the review is that the tumor microenvironment is not a passive backdrop but an actively engineered landscape, and SPP1 is one of its chief engineers. By promoting pro-tumor macrophage polarization, disabling innate immunity, exhausting and excluding T cells, and hardening the extracellular matrix into a physical barrier, SPP1 sits at a convergence point of nearly every mechanism tumors use to hide from the immune system. The authors conclude that targeting the SPP1 axis offers a promising strategy for remodeling the tumor microenvironment and enhancing antitumor immunity, a conclusion that is likely to accelerate preclinical and clinical efforts. If those efforts succeed, a molecule named for its abundance in bone may become one of the most important levers for turning immunologically cold tumors into ones that modern immunotherapy can finally heat up.

Subject of Research: The role of secreted phosphoprotein 1 (SPP1) in regulating immunosuppression in the tumor microenvironment and therapeutic strategies targeting the SPP1 axis

Article Title: Reprogramming the tumor immune landscape through SPP1 targeting

Article References: Gao, L., Yang, J., & Teng, Y. (2026). Reprogramming the tumor immune landscape through SPP1 targeting. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03844-x

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03844-x

Keywords: SPP1, osteopontin, tumor microenvironment, tumor-associated macrophages, cancer-associated fibroblasts, immune evasion, T cell exclusion, immune checkpoint inhibitors, CD44, integrins, lipid nanoparticles, cancer immunotherapy