Dana-Farber researchers identified interferon‑gamma signaling within tumor-associated myeloid cells as a driver of resistance to immune checkpoint inhibitors in renal cell carcinoma, revealing a myeloid-centric mechanism that could be targeted to restore sensitivity. Separately, UCLA researchers showed that DNA copy-number alterations drive melanoma resistance to immunotherapy, mapping genomic changes that blunt immune responses. Both studies provide mechanistic insights into why some tumors fail checkpoint blockade: immune-cell signaling within the tumor microenvironment and tumor-intrinsic genomic instability. They suggest complementary therapeutic strategies—modulating myeloid signaling pathways and targeting genomic drivers or vulnerabilities—to overcome resistance. These findings will direct biomarker development and combination trial design, shaping next-generation immune-oncology approaches that pair checkpoint inhibitors with agents addressing myeloid dysfunction or genomic escape mechanisms.