Language

English

Publication Date

11-25-2025

Journal

Nature Communications

DOI

OI: 10.1038/s41467-025-65462-z

PMID

41290625

PMCID

PMC12647744

PubMedCentral® Posted Date

11-25-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here we report the results of a phase II clinical trial (NCT03274258) of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in patients with RMC, with objective response rate as primary outcome. Enrollment was halted for futility at a prespecified interim analysis as all 10 treated patients experienced rapid disease progression. 5/10 met radiological criteria for hyperprogression and median progression-free survival (secondary outcome) was 1.38 months (95% confidence interval: 1.28, 1.60). In a post-hoc single-cell RNA sequencing analysis, data from patients with RMC before and after nivolumab plus ipilimumab treatment indicated that immune checkpoint therapy (ICT) triggered an interferon-γ response that induced a "myeloid mimicry" program in tumor cells, regulated by the CEBPB / p300 axis and linked to proliferation and hyperprogression. In preclinical experiments using an immunocompetent somatic mosaic genetically engineered mouse model of RMC, combination ICT accelerated tumor growth while activating myeloid-affiliated transcriptional circuits. Selective pharmacologic inhibition of p300 suppressed this program and restored sensitivity to ICT. These findings reveal an adaptive mechanism of resistance to ICT in RMC and support targeting master myeloid regulators to enable therapeutic benefit.

Keywords

Ipilimumab, Nivolumab, Humans, Animals, Kidney Neoplasms, Mice, Female, Male, Middle Aged, Disease Progression, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, Carcinoma, Medullary, Adult, Renal cell carcinoma, Tumour immunology, Cancer immunotherapy

Published Open-Access

yes

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