MODIFIED EXOSOMES FOR ENHANCED CANCER TREATMENT

Cancer immunotherapy, utilizing the body's immune system to target cancer cells, has advanced significantly. However, challenges persist in achieving optimal clinical outcomes. Recent research highlights immune cell-derived exosomes' potential in enhancing antitumor immune responses. Yet, natural exosomes have limitations in clinical use. Technological advancements allow for exosome modification, boosting their functions and targeting abilities. Engineered exosomes show promising antitumor effects, promising improved cancer immunotherapy.  

Cancer immunotherapy targets tumors by stimulating the immune system, which is governed by innate and adaptive immune cells. New immunotherapies have developed, including monoclonal antibody-based immune checkpoint blockades and chimeric antigen receptor (CAR)-T cell treatment. Exosomes, which are tiny, endogenous transporters, have emerged as interesting targets for cancer immunotherapy. IEXs, which can alter the antitumor immune response, have showed promise in cancer therapy. Exosome modification methods, including as genetic engineering and cargo transfer, have been developed to increase their therapeutic value.

Modification strategies of IEXs for cancer immunotherapy:

Cytokines have an important role in modulating immune cell function, and cytokine pretreatment of parental cells can improve therapeutic efficiency. Preconditioning DC-derived exosomes (DEXs) with interferon-γ (IFN-γ) enhances natural killer cell-mediated antitumor effectiveness in NSCLC patients. Exosomes have become a popular medication delivery strategy due to their low toxicity, great biocompatibility, and stability. Cargo can be packed utilizing both endogenous and exogenous loading processes, including electroporation, sonication, freeze-thaw cycles, extrusion, and saponin treatment. It has been hypothesized that genetic editing of the exosome surface can improve tumor-specific targeting in exosome-based cancer immunotherapy. Membrane-tethering technology for proteins (MTFP) has been proposed as a viable technique for displaying bioactive proteins on the cell surface, hence improving exosome anticancer activity. 

Chemical alteration of exosome surfaces can include both natural and synthetic ligands, and click chemistry is a useful covalent surface engineering approach. Noncovalent coupling, such as electrostatic and hydrophobic interactions, is an approach for long-term alteration of biological membranes. immunity surveillance and response rely heavily on exosomes produced by innate immunity cells such as DCs, NK cells, macrophages, and neutrophils. Modified innate IEXs can enhance their intrinsic anticancer characteristics, making them intriguing candidates for cancer immunotherapy. DEXs, the most potent APCs, elicit antigen-specific immune responses and serve as a link between the innate and adaptive immune systems. DEXs have more stability and ease of manipulation than DCs, prompting numerous initiatives to improve their therapeutic efficacy. Exosomes generated from NK cells have demonstrated great antitumor activity in cancer immunotherapy, killing cancer cells such as melanoma and breast cancer. They have been modified to increase anticancer activity in cancer immunology applications like as drug delivery systems (DDS). Surface-engineered exosomes can improve their targeting ability and binding affinity to other drugs, hence increasing their duration of action and stability in vivo. 

M1 macrophage-derived exosomes have gained popularity in cancer immunotherapy for delivering antigens to CD4+ or CD8+ T cells via receptor-ligand interactions. They can also act as adjuvants for anti-tumor therapeutic drugs, increasing their efficacy in cancer treatment. Cancer vaccines have employed modified exosomes produced from M1 macrophages to encapsulate PTX and target IL-4 receptors on M2 macrophages. B cells influence immune cell activity by a variety of ways, including antigen presentation, cytokine release, and supporting costimulatory signals. Exosomes produced by B lymphomas exhibit enhanced immunogenicity and cytotoxicity against Burkitt's lymphoma cells. Modified B cell-derived exosomes have demonstrated promise in cancer therapy. CD4+ T cell-derived exosomes are regarded as prospective molecules for mediating anticancer effects in cancer immunotherapy. They boost CD8+ T cells' anticancer responses and stimulate B cell antibody production. Modified CD4+ T cell-derived exosomes can operate as novel activators of CD8+ T cells, providing a new way to boost antitumor effectiveness in cancer immunotherapy. Exosomes generated from CD8+ T cells have been demonstrated to have anticancer effects, making them a prospective alternative to cell-based therapies for cancer therapy. 

Modified IEXs (deoxygenase-enhancers of peptides) have showed potential in cancer treatment due to their inherent anticancer properties and effective delivery of therapeutic payload. However, clinical studies have restricted their broad use due to issues such as large-scale manufacture, storage, and exosome variability. Exosome purification procedures must be standardized and tested in many cell types for large-scale manufacturing. Long-term storage technology is also critical for maintaining exosome biological activity. More research is needed to address these issues and enhance next-generation exosome-based cancer immunotherapy. Despite these obstacles, customized IEXs show promise in cancer therapy.

REFERENCE

Jung I, Shin S, Baek M-C, Yea K. Modification of immune cell-derived exosomes for enhanced cancer immunotherapy: Current advances and therapeutic applications. Experimental & Molecular Medicine. 2024 Jan 4;56(1):19–31. doi:10.1038/s12276-023-01132-8