Overcoming Immunosuppression in Cancer with Engineered NK Cells

Immunosuppression in the tumor microenvironment (TME) poses a significant obstacle to effective cancer therapy. Tumors use various mechanisms to evade immune responses, such as recruiting suppressive immune cells (e.g., regulatory T cells, myeloid-derived suppressor cells) and secreting suppressive cytokines (e.g., TGF-β and IL-10). Recent studies have shown that engineered NK (natural killer) cells may provide a promising solution to overcome these challenges.

NK cells are engineered to resist the inhibitory effects of the TME. The main technology involves disrupting inhibitory receptor pathways such as PD-1/PD-L1 and NKG2A using gene editing tools such as CRISPR-Cas9. This reprogramming technology restores the cytotoxicity of NK cells, allowing them to more effectively target and destroy cancer cells.

In addition, NK cells can be engineered to express chimeric antigen receptors (CARs) that are designed to recognize specific tumor antigens, providing enhanced specificity and tumor killing capabilities. These CAR-NK cells can not only overcome immunosuppression, but also thrive in complex TME. Cytokine modification (such as IL-15 overexpression) can also enhance the survival and persistence of NK cells within the TME.

Some studies have shown that modified NK cells can be combined with immune checkpoint inhibitors or TME regulation drugs to enhance their therapeutic effects. This dual approach not only combats intrinsic tumor resistance and extrinsic immunosuppression, but also creates a more favorable environment for immune-mediated tumor eradication.

Together, preclinical and early clinical trials have demonstrated that modified NK cells can effectively function in an immunosuppressive environment. Scientists believe that as technology continues to advance, these therapies are expected to become an integral part of the next generation of cancer treatment, providing safer, scalable and more effective solutions for patients with aggressive and resistant tumors.

Reference

[1] Massimo Fantini et al., Frontiers in Immunology 2023 (doi: 10.3389/fimmu.2023.1275904)