Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death-ligand 1 inhibitors in non–small cell lung cancer

The availability of agents targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has transformed treatment of advanced and/or metastatic non–small cell lung cancer (NSCLC). However, a substantial proportion of patients treated with these agents do not respond or experience only a brief period of clinical benefit. Even among those whose disease responds, many subsequently experience disease progression. Consequently, novel approaches are needed that enhance antitumor immunity and counter resistance to PD-(L)1 inhibitors, thereby improving and/or prolonging responses and patient outcomes, in both PD-(L)1 inhibitor-sensitive and inhibitor-resistant NSCLC. Mechanisms contributing to sensitivity and/or resistance to PD-(L)1 inhibitors in NSCLC include upregulation of other immune checkpoints and/or the presence of an immunosuppressive tumor microenvironment, which represent potential targets for new therapies. This review explores novel therapeutic regimens under investigation for enhancing responses to PD-(L)1 inhibitors and countering resistance, and summarizes the latest clinical evidence in NSCLC.