New research presented identifies interferon-induced transmembrane protein 3 (IFITM3) as a critical regulator of immunotherapy sensitivity in small cell lung cancer (SCLC), offering a promising new avenue for overcoming resistance to PD-1/PD-L1 checkpoint blockade.

The research was presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer (WCLC).

SCLC tumours are typically characterised by low expression of major histocompatibility complex class I (MHC-I), which impairs immune recognition and response.

Researchers from the Shanghai Pulmonary Hospital and the University of Pittsburgh have discovered that IFITM3 enhances MHC-I expression by activating NLRC5, a key transcriptional regulator, and promoting its nuclear translocation.

This effect improves antigen presentation and boosts CD8⁺ T cell infiltration and cytotoxicity.

“Our study shows that IFITM3 plays a pivotal role in shaping tumour immunogenicity in SCLC,” said Dr. Xinyu Liu of Shanghai Pulmonary Hospital, Tongji University School of Medicine, China.

“It may serve both as a predictive biomarker for immunotherapy response and a novel therapeutic target.”

Dr. Liu presented a number of significant findings:

• Strong correlation between IFITM3 and MHC-I expression in multiple real-world SCLC cohorts.
• IFITM3 overexpression upregulated antigen presentation pathways and increased CD8⁺ T cell infiltration.
• IFITM3 expression predicted improved progression-free survival in patients receiving chemoimmunotherapy.
• A novel compound, ethyl gallate (EG), induced IFITM3 and sensitised tumours to PD-1 blockade in preclinical models.

“Our study suggests that pharmacological induction of IFITM3 could represent a new strategy to improve clinical outcomes for patients with SCLC. Future clinical research may validate IFITM3 as both a biomarker and a therapeutic adjunct to current immunotherapy regimens,” Dr. Liu reported.

Source: International Association for the Study of Lung Cancer