Nanomaterial-based strategies overcome PD-1 related intrinsic immune resistance.

Immune-checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have substantially improved outcomes for patients with multiple cancer types; however, primary (intrinsic) resistance remains common and limits durable responses. Mechanistically, such resistance can arise from impaired interferon-γ signaling (including Janus kinases-signal transducer and activator of transcription dysfunction), tumor-intrinsic oncogenic pathway alterations [e.g., phosphatase and tensin homolog (PTEN) loss with downstream phosphoinositide 3-kinase/protein kinase B hyperactivation and Wnt/β-catenin-associated immune escape], and tumor-extrinsic immunosuppression mediated by PD-L1-upregulated suppressive myeloid populations such as myeloid-derived suppressor cells. These pathways converge on reduced T-cell effector function, compromised immune recognition, and reinforcement of an immunosuppressive tumor microenvironment (TME), collectively diminishing the clinical benefit of PD-1/PD-L1 blockade. In this review, we synthesize current evidence on primary (intrinsic) resistance to PD-1/PD-L1 blockade and discuss how nanomaterial-enabled interventions can be mechanistically matched to these resistance determinants. The nanotechnology-based therapeutic strategies were classified as four categories: (i) modulation of resistance-associated signaling pathways; (ii) direct blockade/interception of the PD-1/PD-L1 axis; (iii) immune-checkpoint gene silencing; and (iv) TME reprogramming.