Scientists from Peking University have uncovered a promising strategy for cancer treatment by targeting the protein reticulon-4 (RTN4), which plays a crucial role in regulating endoplasmic reticulum (ER) membrane curvature and triggering pyroptosis, a highly inflammatory form of programmed cell death.
The research, published in Protein & Cell, demonstrates that inducing RTN4 degradation can significantly alter ER membrane morphology, leading to cell death mechanisms that could enhance antitumor immune responses. By using a chemical probe called α-mangostin (α-MG), researchers found they could recruit an E3 ligase to degrade RTN4, causing extensive ER remodeling and activating the caspase-3/GSDME pathway.
In vivo studies revealed that RTN4 knockdown not only inhibited tumor growth but also showed remarkable potential when combined with anti-PD-1 immunotherapy. This discovery suggests a potential new therapeutic approach that could improve cancer treatment efficacy by directly manipulating cellular death mechanisms.
The implications of this research are significant. By identifying RTN4 as a druggable target for pyroptosis, scientists have opened new possibilities for developing small molecule anticancer agents. The study's approach of targeting ER dynamics represents an innovative strategy that could potentially overcome current limitations in cancer immunotherapy.
Dr. Ke-Wu Zeng, a corresponding author of the study, emphasized the transformative nature of these findings, noting that targeting RTN4 could offer a prospective strategy for anticancer immunotherapy by inducing potent antitumor immune responses.
