Exploring tumor-derived exosomes as promising antigenic platforms: novel vaccine and immunotherapy strategies for “cold” colorectal cancer

Abstract

Colorectal cancer (CRC) remains a formidable clinical challenge, largely due to the prevalence of microsatellite-stable tumors characterized by an immunologically “cold” tumor microenvironment (TME) that is resistant to immune checkpoint inhibitors (ICIs). Tumor-derived exosomes (TEXs) play a paradoxical dual role in this landscape. Native TEXs actively orchestrate immune evasion by delivering immunosuppressive molecules, such as programmed cell death 1 ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), which impair cytotoxic T-cell function and promote the expansion of regulatory T cells and M2 macrophages. Conversely, TEXs possess inherent biocompatibility and naturally harbor a broad repertoire of tumor-associated antigens (TAAs) and major histocompatibility complex (MHC) molecules, positioning them as potential cell-free platforms for cancer vaccination. Current evidence demonstrates that native TEXs establish their immunosuppressive niche primarily through the systemic PD-1/PD-L1 axis and microRNA-driven macrophage polarization. However, preclinical studies indicate that exosome engineering strategies—such as masking surface PD-L1 or loading vesicles with immune adjuvants, siRNAs, or CRISPR components—can effectively neutralize these suppressive traits and amplify antigen presentation. While clinical data in CRC remain limited, engineered TEXs exhibit strong preclinical promise for synergizing with ICIs to reprogram cold CRC into immune-responsive “hot” tumors. Advancing these early-stage therapies from the bench to the clinic will require overcoming significant translational hurdles, particularly regarding standardized isolation protocols and scalable manufacturing.