ArticleNature communications2021
9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 143 papers, 1 of them a synthesis that pooled it.
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Who cites it
143 citing papers in PubMed, 1 synthesis or guideline pooled it, 211 citations in OpenAlex.
- Efficacy and safety analysis of immune checkpoint inhibitors combined with chemotherapy in the treatment of advanced triple-negative breast cancer: an umbrella meta-analysis.Frontiers in oncology · 2026Pooled it
- Adjuvant nivolumab in muscle-invasive urothelial carcinoma: exploratory biomarker analysis of the randomized phase 3 CheckMate 274 trial.Nature medicine · 2025Trial
- Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial.Nature communications · 2025Trial
- A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.Nature communications · 2024Trial
- Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.JCO precision oncology · 2024Trial
- Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial.Nature communications · 2023Trial
- MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.Nature communications · 2022Trial
- A Boveri perspective on cancer biomarker testing using artificial intelligence.NPJ precision oncology · 2026Review
- Acquired Resistance to the PRMT5 Inhibitor Confers Collateral Sensitivity to MEK Inhibition inBiomolecules · 2026Article
- Development of an immunocompetent cutaneous squamous cell carcinoma model identifies VISTA and CTLA-4 as targetable immune checkpoints.Journal for immunotherapy of cancer · 2026Article
- Comprehensive Genomic and Transcriptomic Characterization of MTAP Loss across Advanced Solid Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Observational
- MTAP Deficiency as a Metabolic Vulnerability in Cancer: Implications for Synthetic Lethal Therapy.Cancer science · 2026Review
- The detection of MTAP loss in non-small cell lung cancer: a novel biomarker with therapeutic implications.Translational lung cancer research · 2026Article
- Presenting features and outcomes to standard systemic therapies in patients with MTAP-deleted advanced non-small cell lung cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Role of methionine metabolism in cancer: recent advances in molecular mechanisms and therapeutic implications.Experimental hematology & oncology · 2026Review
- GSDME-mediated pyroptosis modulates the immunosuppressive microenvironment in lung adenocarcinoma.Acta pharmacologica Sinica · 2026Article
- WAC is associated with malignant phenotypes and Wnt/β-catenin pathway activity in liver cancer cells.Translational cancer research · 2026Article
- Prevalence of heterozygous and homozygous 9p21 deletions in human cancer: a tissue microarray study on 4,999 tumors from 125 different tumor types.Molecular medicine (Cambridge, Mass.) · 2026Article
- Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities.Science advances · 2026Article
- The Evolving Landscape of Immune Regulation and Immunotherapy in Cholangiocarcinoma and Biliary Tract Cancer.Cancers · 2026Review
83 more citing papers are in PubMed but not listed here.
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Authors and funding
32 authors at 6 institutions in 2 countries.
Funding
Abstract
Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.