Molecular basis for developing tumor-targeted siRNAs for future immunotherapy

INTRODUCTION: Certain immune signaling pathways contribute to cancer progression by promoting tumor immune evasion through immune checkpoint activation, immunosuppressive cytokine production, metabolic depletion, and altered intracellular signaling. Small interfering RNAs (siRNAs) provide a programmable strategy for selectively silencing genes involved in tumor immune evasion and immunosuppression, offering a targeted approach to enhance antitumor immunity. AREAS COVERED: This review highlights the rationale for targeting immune regulatory factors with siRNA in cancer immunotherapy. Key targets include immune checkpoints (e.g. programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4), immunosuppressive mediators (e.g. transforming growth factor beta 1 and indoleamine 2,3-dioxygenase 1), and intracellular regulators (e.g. suppressor of cytokine signaling 1 and signal transducer and activator of transcription 3). Preclinical and early clinical studies show that silencing these targets restores T-cell activity, improves antigen presentation, remodels the tumor microenvironment, and enhances anti-tumor immunity. Additionally, advances in siRNA delivery methods are accelerating clinical translation. EXPERT OPINION: By silencing genes involved in immune suppression, siRNAs can restore T cell activation and improve the efficacy of cancer vaccines and adoptive cell therapies. However, significant challenges remain, including achieving efficient cell-specific delivery and minimizing off-target effects.