Researchers from the Dana-Farber Cancer Institute have uncovered how certain immune system signals may make kidney tumors resistant to immunotherapy. Their work focuses on renal cell carcinoma (RCC), a common form of kidney cancer that is often treated with immune checkpoint blockade (ICB) therapy. While ICB can be highly effective, many patients do not respond, and understanding why has become a key challenge in cancer research.

The research team used single-cell RNA sequencing to map how type I and type II interferons (IFNs), molecules that regulate immune responses, affect different cells in the tumor microenvironment. They discovered that macrophages, a type of immune cell, showed strong responses to IFN signaling, producing inhibitory ligands and immune checkpoint molecules that can suppress the activity of cancer-fighting T cells. In contrast, the tumor cells themselves were much less responsive to these signals.

Further analysis revealed that a specific pattern of IFNγ (interferon-gamma) signaling in myeloid cells, but not in tumor cells, was linked to primary resistance to ICB therapies when combined with anti-VEGF treatments. Laboratory experiments confirmed that macrophages exposed to IFNγ could directly block T cells from killing RCC tumor cells.

This research highlights how immune cell behavior, not just tumor cell genetics, can shape a cancer’s resistance to treatment. By identifying these interferon-driven pathways, scientists may be able to develop new biomarkers and therapies that improve responses to immunotherapy in kidney cancer patients.