INTERFERON-INDUCED transmembrane protein 3 (IFITM3) has been identified as a critical regulator of immunotherapy response in small cell lung cancer (SCLC), with new findings showing its potential role as both a predictive biomarker and therapeutic target. The study highlights how IFITM3 enhances tumor immunogenicity, improving outcomes for patients receiving checkpoint blockade therapies.
SCLC is known for its aggressive course and poor survival rates. One of its hallmarks is reduced expression of major histocompatibility complex class I (MHC-I), which limits immune recognition. Investigators from the Shanghai Pulmonary Hospital and the University of Pittsburgh reported that IFITM3 can counteract this limitation by activating the transcriptional regulator NLRC5 and promoting its movement into the nucleus. This process boosts MHC-I expression, strengthens antigen presentation, and facilitates CD8⁺ T cell infiltration and cytotoxicity.
The research team presented multiple lines of evidence supporting IFITM3’s role in shaping the immune landscape of SCLC. Across several real-world patient cohorts, IFITM3 expression strongly correlated with MHC-I levels. In preclinical models, IFITM3 overexpression increased antigen presentation pathways and enhanced T cell responses. Clinical observations showed that higher IFITM3 expression predicted improved progression-free survival in patients treated with combined chemoimmunotherapy.
A further advance was the identification of ethyl gallate, a small molecule that induces IFITM3 expression. In experimental settings, ethyl gallate sensitized tumors to PD-1 blockade, suggesting a possible route to overcoming primary resistance to immune checkpoint inhibitors. These findings point toward pharmacological strategies that could extend the benefits of immunotherapy to a greater proportion of patients with SCLC.
The lead investigator emphasized that IFITM3 may serve as a biomarker to identify patients most likely to respond to immunotherapy, while also representing a target for therapeutic intervention. Future clinical trials will be needed to confirm these results and evaluate the safety and efficacy of IFITM3-inducing compounds in humans.
Reference: International Association for the Study of Lung Cancer (IASLC). New research identifies IFITM3 as key driver of immunotherapy response in small cell lung cancer. September 9 2025. Available at: https://www.iaslc.org/iaslc-news/press-release/new-research-identifies-ifitm3-key-driver-immunotherapy-response-small. Last accessed: September 11 2025.
