Beyond target presence: A cross-cancer contextual framework for siRNA therapeutics in solid tumors

Small interfering RNA (siRNA) has achieved clinical success in liver-directed therapies, but its translation to solid tumors remains limited by heterogeneous delivery and context-dependent target dependence. This review compares non-small cell lung cancer, pancreatic ductal adenocarcinoma, breast cancer, glioblastoma, and hepatocellular carcinoma across four interconnected dimensions: resistance networks, tumor microenvironmental reprogramming, metastatic progression, and delivery-system design. We examine how bypass signaling and phenotypic plasticity influence target selection, how stromal and immune compartments shape therapeutic responses, and how disease stage and organ-specific barriers alter delivery requirements. We then assess representative clinical RNA interference programs to distinguish evidence of tissue exposure and target engagement from antitumor activity and established clinical benefit. Across these settings, tumor accumulation does not establish productive cytosolic delivery, and target knockdown alone does not ensure durable disease control. We propose a context-dependent framework that aligns functional target dependence with the intended cell population, tissue environment, treatment timing, and delivery route. Priorities include resistance-informed combinations, prospective validation of delivery biomarkers, repeat-dose safety assessment, and carrier designs whose functional benefits justify their manufacturing complexity. By linking mechanistic comparison with clinical evidence, this review identifies testable criteria for selecting patients, evaluating functional delivery, and advancing siRNA therapeutics for solid tumors.