Abstract
<title>Abstract</title> <p>Pancreatic ductal adenocarcinoma (PDAC) is lethal in ~88% of patients. Immunotherapy has revolutionized cancer therapy for many cancer types; however, PDAC survival rates remain unchanged. Low tumor mutation burden, inefficient antigen presentation, limited response rates to standard-of-care (SoC) therapy, acquired resistance, and a profoundly immunosuppressive microenvironment constrain the efficacy of immunotherapy. Advances in nanotechnology-based vaccines have enabled the precise delivery of mRNA and antigens, thereby potently activating the immune system and opening new avenues for treating PDAC. Here, we report a mannose-grafted nanovaccine (NV) platform that co-packages the gastrointestinal cancer-overexpressed CEACAM5 (CEA5), and immune adjuvants to sensitize antigen-presenting cells (APCs) and enhance their antigen-presenting capacity, promoting efficient lymph node priming and robust CD4⁺ and CD8⁺ T-cell activation. Our NV induced substantial remodeling of the PDAC microenvironment, reflected by increased CD8+ T-cell infiltration and T-cell memory, while decreasing T-cell exhaustion, cancer-associated fibroblast abundance, desmoplasia, pro-tumorigenic metabolic pathways, and angiogenic signaling. NV monotherapy significantly suppressed primary tumor growth and extended survival in a PDAC mouse model. In a tumor resection model, NV-treated mice showed reduced local tumor recurrence and complete prevention of hepatic metastasis. Combination therapy with SoC and a KRAS inhibitor further enhanced tumor control and survival compared with either monotherapy. The translational potential of the NV is supported by patient-derived models, in which NV-pulsed APCs generated functional antigen-specific T cells capable of killing tumor cells. Notably, NV also demonstrated robust antitumor efficacy in a mouse colorectal cancer model, delaying tumor progression and prolonging survival, highlighting the translational potential of this modular platform across gastrointestinal cancers. Collectively, this work establishes a modular and translationally relevant NV platform capable of converting immune-refractory PDAC into a therapeutically responsive disease by amplifying endogenous antitumor immunity.</p>