ArticleCancer immunology research2025
SPP1+ Tumor-Associated Macrophages Drive Immunotherapy Resistance via CD8+ T-cell Dysfunction in Clear-Cell Renal Cell Carcinoma.
Article in Cancer immunology research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Nivolumab plus ipilimumab induce hyper-progression in renal medullary carcinoma: results of a phase II trial and preclinical evidence.Nature communications · 2025Trial
- A placental and fetal liver TGFβ signaling axis drives fetal immunosuppression in maternal obesity.iScience · 2026Article
- Tissue-Resident Macrophage in Inflammation and Cancer.MedComm · 2026Review
- Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma.Nature communications · 2026Article
- d-serine as a metabolic immune checkpoint in the tumour microenvironment.EBioMedicine · 2026Article
- The tumoural landscape of lymphocytes and immune pathways in immunotherapy-treated melanoma patients.Genes and immunity · 2026Article
- Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma.Cancer cell · 2026Article
- Tumour-Derived Extracellular Vesicles Reprogramme Tumour-Associated Macrophages Into Immunosuppressive Phenotype via NOD1 Signalling in Clear Cell Renal Cell Carcinoma.Journal of extracellular vesicles · 2026Article
- Lactate-Driven IL8+ Tumor-Associated Macrophages Mediate Immunosuppression and Resistance to Immunotherapy in Clear-Cell Renal Cell Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- SpaPheno: linking spatial transcriptomics to clinical phenotypes with interpretable machine learning.Genome medicine · 2026Article
- Immune Escape in Renal Cell Carcinoma: Latest Research and Treatment Strategies.International journal of molecular sciences · 2026Review
- Single-Cell Mapping Reveals MIF-Centered Immunoregulatory Networks in Colorectal Cancer.International journal of molecular sciences · 2026Article
- A bibliometric analysis of resistance to PD-1/PD-L1 inhibitors.Frontiers in immunology · 2026Article
- Molecular innate immune programs of tumor-associated macrophages in immune checkpoint blockade resistance: a staged framework from suppressive circuitry to translational bottlenecks.Frontiers in immunology · 2026Review
- Transcriptional activation of ALOX5 by c-Myc drives malignant progression and M2 macrophage polarization in clear cell renal cell carcinoma.American journal of cancer research · 2026Article
- Remodeling the tumor immune microenvironment: mechanisms of crosstalk between regulated cell death macrophages.Frontiers in immunology · 2026Review
- Innate immune signaling-driven myeloid remodeling in cancer: inflammatory amplification, immune suppression, and therapeutic targeting.Frontiers in immunology · 2026Review
- Preclinical exploration and current clinical applications of immunotherapeutic strategies for hepatocellular carcinoma.Frontiers in immunology · 2026Review
- The CXCL9/SPP1 polarity axis in tumor-associated macrophages: immunoregulatory and prognostic significance in non-small cell lung cancer.Frontiers in immunology · 2026Article
- Tumor-Promoting Crosstalk of MMP11⁺ Fibroblasts and SPP1⁺ Macrophages Drive Poor Prognosis in Breast Cancer: Integrated Multi-Omics Analysis.ImmunoTargets and therapy · 2026Article
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Authors and funding
10 authors.
Funding
Abstract
Tumor-associated macrophages (TAM) are key regulators of tumor immunity. With advances in single-cell analyses, secreted phosphoprotein 1 (SPP1)-positive TAMs have been observed across multiple tumor sites. However, their clinical relevance and phenotypic characteristics in clear-cell renal cell carcinoma (ccRCC) have not been comprehensively delineated. Using patient-level data from two in-house cohorts (n = 355), we explored the relationship between SPP1+ TAM infiltration and therapeutic response and prognosis in ccRCC. Four publicly available datasets consisting of 1,741 patients with ccRCC were included for external validation. Cytometry by time-of-flight and flow cytometry were utilized to phenotype SPP1+ TAMs and establish their impact on CD8+ T cells. Furthermore, we established an ex vivo culture system to test the potential therapeutic value of targeting SPP1 alone and in conjunction with PD-1 inhibitors in ccRCC. We found that patients with high SPP1+ TAM infiltration exhibited worse response to immunotherapy and dismal prognosis in ccRCC. SPP1+ TAMs exhibited an immunosuppressive and protumor phenotype, and were related to impaired effector function and terminal differentiation of CD8+ T cells. Blockade of SPP1 mitigated the protumor tumor microenvironment and reinvigorated CD8+ T-cell function. Combining PD-1 blockade with SPP1 blockade boosted the expansion of CD8+ T cells and enhanced antitumor efficacy. Together, these data indicate that elevated infiltration of SPP1+ TAMs is related to worse response to immunotherapy and dysfunction of CD8+ T cells in ccRCC. We conclude that SPP1 may serve as a potential therapeutic target in ccRCC.
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