Proteolysis targeting chimera (PROTAC) for epidermal growth factor receptor enhances anti‐tumor immunity in non‐small cell lung cancer

Abstract While immunotherapy has dramatically revolutionized the treatment of non‐small cell lung cancer (NSCLC), it still faces challenges such as low therapeutic efficacy and immune‐related adverse events, indicating that safe and effective approaches to enhance NSCLC immunotherapy are still highly demanded. Epidermal growth factor receptor (EGFR) is an established target for molecularly targeted therapy of NSCLC. Overexpression and activating mutations of EGFR can promote the resistance of NSCLC to immunotherapy via upregulating inhibitory immune checkpoints such as programmed death receptor ligand 1 (PD‐L1) and indoleamine‐2,3‐dioxygenase‐1 (IDO1). Thus, therapeutic inhibition of EGFR also holds promise in modulating the immune microenvironment to advance NSCLC immunotherapy. In this study, we employed a proteolysis targeting chimera (PROTAC) that degrades EGFR L858R to investigate its potential in dually inhibiting PD‐L1 and IDO1 to potentiate the anti‐tumor immunity in NSCLC. We demonstrated that PROTAC significantly downregulated the protein levels of both PD‐L1 and IDO1 in NSCLC H3255 cell and tumor. We also confirmed that PROTAC significantly suppressed the H3255 tumor growth and enhanced the anti‐tumor immune response in H3255 tumor. Overall, our study provides a novel strategy for future NSCLC therapy.