Immunotherapy resistance in kidney cancer driven by myeloid cell signaling

RESEARCH SUMMARY

Study Title: Myeloid cells mediate interferon-driven resistance to immunotherapy in

advanced renal cell carcinoma

Publication: Immunity – October 2025

Corresponding Dana-Farber Cancer Institute Author: Eliezer M. Van Allen, MD

Summary: Immunotherapy with immune checkpoint inhibitors is standard first-line treatment for advanced renal cell carcinoma (RCC), but not every patient responds. An open question is whether specific patterns of immune signaling, specifically interferon signaling, influence the effectiveness of immune checkpoint inhibitors against the disease. This study combined single cell RNA sequencing data from multiple RCC patient cohorts to learn more about patterns of interferon signaling across cell types in tumors and tumor microenvironments. The team used computational modeling tools to characterize interferon signaling dynamics and identify key patterns. They then looked across clinical trial studies to determine if any of these patterns correlated with resistance to immune checkpoint inhibitors. They found that interferon-gamma (IFNγ) signaling in immune cells called myeloid cells corresponds with resistance to immunotherapy, while IFNγ signaling in other cells does not.

Significance: Biomarkers used in other cancers to predict a response to immune checkpoint inhibitors do not work for RCC. The results of this study could help investigators discover biomarkers to help identify which patients will be likely respond to immunotherapy and which might benefit from a different treatment strategy. Further, the study results point to a potential target for therapies that sensitize RCC tumors to immunotherapy.

Funding: Novartis, National Institutes of Health, U.S. Department of Defense, Louis Goodman and Alfred Gilman Yale Scholar Fund, Yale Cancer Center.

Contact: Victoria Warren, victoria_warren@dfci.harvard.edu