Oral Nano-vaccines for cancer immunotherapy: mechanisms, barriers, and the oral-GALT-tumor immune axis

Oral nano-vaccines offer a non-invasive approach for cancer immunotherapy by combining gastrointestinal delivery with mucosal immune induction and systemic antitumor immune activation. However, their development remains constrained by antigen degradation in the gastrointestinal tract, mucus entrapment, inefficient M-cell and antigen-presenting cell uptake, mucosal immune tolerance, limited intracellular antigen processing, and interindividual variation in the gut microbiota. In this Review, we propose the “Oral-GALT-Tumor Immune Axis” as a conceptual framework for organizing current evidence on how orally delivered nanovaccines may connect intestinal antigen transport, gut-associated lymphoid tissue (GALT)-mediated immune priming, systemic immune trafficking, and tumor microenvironment modulation. By placing gastrointestinal barriers and GALT activation upstream of distant antitumor immunity, this framework extends conventional discussions of oral vaccination and the cancer-immunity cycle toward the design of oral cancer nanovaccines. We summarize major oral delivery barriers and discuss how lipid-based, polymeric, biomimetic, stimuli-responsive, receptor-targeted, and nanoadjuvant-based platforms may improve antigen protection, intestinal transport, immune-cell targeting, and antigen presentation. We further review protein and nucleic acid-based antigen processing, CD4⁺ and CD8⁺ T-cell activation, humoral responses, macrophage polarization, myeloid-derived suppressor cell modulation, and microbiota-associated immune regulation. Emerging directions, including oral mRNA delivery, virus-like and biomimetic platforms, microbiota-integrated nanomedicines, artificial intelligence-assisted design, and combination with immune checkpoint blockade, are also discussed. Finally, we highlight unresolved challenges in delivery efficiency, oral tolerance, microbiota variability, long-term safety, immune readout standardization, manufacturability, and clinical translation. Together, these discussions outline both the promise and current limitations of oral nanovaccines and may help guide the rational design and translational evaluation of next-generation cancer immunotherapy platforms.