NK/DC crosstalk-modulating antitumor activity via Sema3E/PlexinD1 axis for enhanced cancer immunotherapy

The complex relationship between natural killer (NK) cells and dendritic cells (DCs) within the tumor microenvironment significantly impacts the success of cancer immunotherapy. Recent advancements in cancer treatment have sought to bolster innate and adaptive immune responses through diverse modalities, aiming to tilt the immune equilibrium toward tumor elimination. Optimal antitumor immunity entails a multifaceted interplay involving NK cells, T cells and DCs, orchestrating immune effector functions. Although DC-based vaccines and NK cells’ cytotoxic capabilities hold substantial therapeutic potential, their interaction is frequently hindered by immunosuppressive elements such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells. Chemokines and cytokines, such as CXCL12, CCL2, interferons, and interleukins, play crucial roles in modulating NK/DC interactions and enhancing immune responses. This review elucidates the mechanisms underlying NK/DC interaction, emphasizing their pivotal roles in augmenting antitumor immune responses and the impediments posed by tumor-induced immunosuppression. Furthermore, it explores the therapeutic prospects of restoring NK/DC crosstalk, highlighting the significance of molecules like Sema3E/PlexinD1 in this context, offering potential avenues for enhancing the effectiveness of current immunotherapeutic strategies and advancing cancer treatment paradigms. Harnessing the dynamic interplay between NK and DC cells, including the modulation of Sema3E/PlexinD1 signaling, holds promise for developing more potent therapies that harness the immune system’s full potential in combating cancer.

NK cells are pivotal in the antitumor response, influencing both innate and adaptive immunity. (1) These first responders identify and destroy tumor cells through activating receptors targeting ligands on compromised cells while sparing healthy cells via inhibitory receptors. (2) NK cells express the CD16 FcγRIII receptor, enabling antibody-dependent cellular cytotoxicity (ADCC), thus enhancing the efficacy of antibody-based cancer treatments like Herceptin and Erbitux. (3) Beyond direct cytotoxicity, activated NK cells release cytokines such as IFN-γ and TNF-α, which recruit other immune cells and promote an inflammatory tumor microenvironment, facilitating immunotherapy. (4) Intratumoral NK cells secrete chemoattractants CCL5, XCL1, and FLT3LG, promoting the formation of stimulatory dendritic cells (cDC1) that activate adaptive immunity. (5) They also recruit T cells via cytokines IL-8, CCL3, and CCL5 and release cytotoxic exosomes containing effector miRNAs and cytokines, underscoring their multifaceted role in tumor immunity.