Transforming cancer immunotherapy: Overcoming immunosuppression in tumors via gene silencing techniques based on nanoparticles

Immunotherapy has transformed cancer treatment, but the tumor immune microenvironment (TIME) is highly immunosuppressive, limiting the effectiveness of immunotherapy and leading to inadequate clinical outcomes. Shifting the focus from the traditional tumor-cell-centered view to recognizing the TIME's critical role in cancer progression highlights the complex tumor ecosystem that facilitates tumor growth and metastasis. Tumor cells use different tactics to avoid the immune system, with immunosuppressive cells' expansion being a critical mechanism. These cells encompass regulatory T lymphocytes (Tregs), myeloid-derived suppressor cells (MDSCs), type-2 tumor-associated macrophages (TAM2), and cancer-associated fibroblasts (CAFs), all of which significantly suppress innate and adoptive anticancer immunity. There has recently been a growing interest in gene-silencing strategies that target these immunosuppressive cells. These strategies aim to silence genes that modulate the immunosuppressive TIME, either at the mRNA level (using siRNAs and antisense oligonucleotides (AsO)) or the DNA level (using CRISPR/Cas to edit mutated sequences). However, their effectiveness is limited by therapeutic genes' stability and transfection capabilities. The intersection of nanotechnology with these strategies holds promise for delivering these genes to modulate the TIME and improve immunotherapeutic responses. The objective of this review is to bring attention to the present comprehension of immunosuppressive TIME, discover the hindrances to gene silencing methods, and investigate the possibility of utilizing nanoparticle-based transportation systems to overcome these obstacles. © 2024 Elsevier B.V.