Local PD-1/PD-L1 RNAi to complement immune checkpoint blockade: the dual-hit hypothesis in cutaneous malignancies

Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICIs) have substantially improved outcomes in advanced skin malignancies. However, many patients still show resistance, experience immune-related adverse events (irAEs), or have uneven antibody penetration into tumors. Small interfering RNAs (siRNAs) provide an alternative means of targeting the same pathway by promoting RNA-induced silencing complex (RISC)-mediated degradation of PD-1/PD-L1 transcripts rather than blocking the corresponding proteins with antibodies. We propose that intratumoral siRNA could reduce PD-1/PD-L1 expression in treated tumors and alter the local immune microenvironment, while systemic ICI could extend checkpoint blockade beyond the injected lesion. We refer to this strategy as the Dual-Hit hypothesis. This article examines its mechanistic basis and summarizes the available preclinical evidence and early clinical experience, including the first-in-human study of PH-762. It also considers the delivery, intracellular, and safety-related factors that may affect clinical development. Whether this combination can improve antitumor activity over ICI alone, alter treatment requirements, or benefit patients with ICI-refractory disease remains unknown and requires clinical testing.