SAN DIEGO — Researchers at the University of California San Diego discovered that microRNA-25 drives resistance to immune checkpoint therapy by suppressing a protein called Syndecan-3, and blocking microRNA-25 improved immunotherapy response in mouse cancer models.
Immune checkpoint therapy is a type of cancer immunotherapy that helps the immune system recognize and attack tumors. However, many cancers either fail to respond to this treatment or become resistant over time. Scientists have been investigating how the tumor microenvironment—a network of cells and signals surrounding tumors that can weaken immune cells and protect cancer from treatment—contributes to this resistance.
The UC San Diego team examined whether microRNAs play a role in creating a treatment-resistant tumor microenvironment. They identified microRNA-25 (miR-25) as a candidate because its levels changed in tumors that responded to immunotherapy. In mouse cancer models, blocking miR-25 did not affect tumor growth on its own but improved tumor response to immunotherapy. Removing miR-25 reshaped the tumor microenvironment and activated several anti-tumor immune responses.
The researchers found that miR-25 suppresses Syndecan-3 (SDC3), a protein involved in immune regulation. Editing the miR-25 binding site on SDC3 restored the protein’s activity and reproduced the therapeutic effects observed when miR-25 was deleted. This suggests the miR-25–SDC3 pathway may be a driver of immunotherapy resistance.
According to the study, therapies targeting the miR-25–SDC3 pathway could help convert immunotherapy-resistant “cold” tumors—those with low immune cell infiltration—into more immune-active “hot” tumors. The research was 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. The study was published on May 20, 2026, in Nature Communications. The journal reference is Zhu, Z., et al. (2026). microRNA-25 drives immune checkpoint therapy resistance by repressing innate and humoral immunity via Syndecan-3. Nature Communications. DOI: 10.1038/s41467-026-73339-y.