Targeting microRNA pathway helps overcome cancer immunotherapy resistance

Immune checkpoint therapy, a type of cancer immunotherapy that helps the immune system recognize and attack tumors, has transformed cancer treatment. While these therapies can produce long-lasting benefits for some patients, many cancers either fail to respond or become resistant over time. One major challenge is the tumor microenvironment - the network of cells and signals surrounding tumors that can weaken immune cells and protect cancer from treatment. This protective environment can act like a shield that prevents immunotherapy from working effectively.

Researchers at University of California San Diego investigated whether microRNAs - small RNA molecules that help control gene activity - play a role in creating this treatment-resistant environment. The team focused on microRNA-25 (miR-25), which stood out after analyses showed that its levels changed in tumors that responded to immunotherapy. Across several mouse cancer models, blocking miR-25 did not significantly affect tumor growth on its own, but it greatly improved how well tumors responded to immunotherapy.

Further analyses showed that removing miR-25 reshaped the environment around the tumor and activated several anti-tumor immune responses. Removing miR-25 appeared to help the immune system attack cancer cells by changing the environment surrounding tumors. Researchers identified a mechanism involving a protein called Syndecan-3 (SDC3), which miR-25 suppresses. Editing the miR-25 binding site restored SDC3 activity and reproduced the therapeutic effects seen with miR-25 deletion, suggesting this pathway may be a critical driver of treatment resistance.

The findings suggest that future therapies targeting the miR-25–SDC3 pathway could help convert immunotherapy-resistant "cold" tumors into more immune-active "hot" tumors that respond better to treatment. The work may eventually help make immunotherapy effective for more cancer patients.

The study, led by Tariq Rana, PhD, Distinguished Professor and chair of the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine and member of the Moores Cancer Center, was published on May 20, 2026, in Nature Communications.