Exploring the Potential of Receptor Silencing in the Tumor Microenvironment by RNA Interference

Cancer is a heterogeneous disease caused by genetic and epigenetic factors, leading to alterations in signaling pathways and regulatory processes. Overall, the more commonly employed conventional treatments present side effects and resistance. Due to the diverse cellular composition of the tumor microenvironment, inhibition of cell communication by RNA interference (RNAi) has emerged as a strategy to regulate the expression of receptors linked to carcinogenesis. This review examines RNAi-mediated receptor silencing as a strategy to modify the tumor microenvironment, primarily in tumor cells, enhancing its vulnerability to immune cell destruction and reducing resistance to conventional therapies. In the tumor microenvironment, the silencing of immune checkpoints like PD-1 and CTLA-4 has demonstrated the ability to restore T cell function and enhance the efficacy of adoptive cell therapies. Additionally, the targeting of G protein-coupled receptors, including CXCR4, CCR5, and A2aR, as well as growth factor receptors such as VEGFR and EGFR, and interleukin receptors, interferes with pathways that are critical for tumor promotion, resulting in diminished angiogenesis, metastasis, and immunosuppression. These strategies utilize advanced delivery systems, including nanoparticles and exosomes, and show that silencing multiple targets can produce more effective antitumor outcomes than single-target methods, underscoring the significant potential of RNA interference in cancer treatment.