Nanotechnology-Based siRNA Delivery Systems to Overcome Tumor Immune Evasion in Cancer Immunotherapy

Abstract

Immune evasion is a common reason causing the failure of anticancer immune therapy. Small interfering RNA (siRNA), which can activate the innate and adaptive immune system responses by silencing immune-relevant genes, have been demonstrated to be a powerful tool for preventing or reversing immune evasion. However, siRNAs show poor stability in biological fluids and cannot efficiently cross cell membranes. Nanotechnology has shown great potential for intracellular siRNA delivery in recent years. Nano-immunotherapy can efficiently penetrate the tumor microenvironment (TME) and deliver multiple immunomodulatory agents simultaneously, which appears to be a promising method for combination therapy. Therefore, it provides a new perspective for siRNA delivery in immunomodulation and cancer immunotherapy. The current advances and challenges in nanotechnology-based siRNA delivery strategies for overcoming immune evasion will be discussed in this review. In addition, we also offer insights into therapeutic options, which may expand its applications in clinical cancer treatment.

Keywords: immune evasion; immunotherapy; nanoparticles; small interfering RNA; tumor microenvironment.

Figure 1

The mechanism of nanotechnology-based siRNA delivery systems. Utilizing delivery materials, siRNA can be delivered directly into the cell. The siRNA is integrated into the RNA-induced silencing complex (RISC) and the sense (passenger) strand is degraded by the RISC protein Argo-2. The remaining antisense strand acts as a guide for recognizing the complementary messenger RNA. The activated RISC–siRNA complex binds to and degrades the target mRNA, leading to the silence of the target gene.

Figure 2

Tumor cells have evolved various strategies for evading immune responses. (A) Downregulation of tumor antigens: Certain malignancies lack pre-existing tumor T cell infiltration, allowing them to escape immunosurveillance due to low tumor antigen expression levels, resulting in inadequate APC recruitment and activation. (B) Weak immunogenicity: Immune selection permits tumors with weak immunogenicity to avoid immune surveillance and grow preferentially, and the weak immunogenicity of tumor antigens may be owing to incorrect or non-expression of costimulatory molecules on tumor cells. (C) Downregulation of MHC-I expression: By evading immune identification by tumor cells, the ability of tumor-associated antigen (TAA)-specific CTLs to kill cancer cells is compromised.

Figure 3

Schematic view of the TME. Tregs exert immunosuppressive effects via the release of IL10, IL-35, PFN, and GzmB. The preponderance of M2-like TAMs in the TME promotes tumor immune evasion. TAMs suppress the immune system in a variety of ways, including the release of IL-10 and TGF-β, activation of the IDO, and overexpression of the PD-L1 checkpoints. MDSCs limit CD8+ T cell and natural killer cell responses via arginine, NO, ROS, and TGF-β.

Figure 4

Targeted delivery of siRNA to MDSCs and Tregs. Depletion of Tregs and MDSCs or suppression of their immunosuppressive effects may restore the antitumor activity of effector T cells, resulting in cancer cells’ death.

Figure 5

Targeted delivery of siRNA to TAMs. Altering the polarization of TAMs or impairing the survival and function of TAMs to achieve the elimination of immune evasion.

Figure 6

Diagrammatic illustration of immune checkpoint blockade therapies. Inhibiting the ligand–receptor interaction of PD-1/PD-L1 to prevent the activation of PD-1/PD-L1 signaling pathway, leading to T cell activation and reduction of tumor cell proliferation.

Figure 7

Diagrammatic illustration of the ICD mechanism. ICD-inducing strategies promote APC activation and priming of tumor-specific CD8+ T cells through the release of tumor antigens, PAMPs, and DAMPs, such as CRT, HSP70, HSP90, and HMG1.