Albumin-binding nanobody cancer vaccines coordinate lymphatic T cell priming and inflammatory remodeling of the tumor microenvironment

Abstract Cancer vaccines can generate tumor-specific T cells, but their efficacy against solid tumors is limited by an immunosuppressive tumor microenvironment (TME). To address this challenge, we developed nAlb-Vax, an albumin-binding nanobody vaccine platform designed to coordinate T cell priming in the lymphatic system with inflammatory remodeling of the TME. nAlb-Vax combines nanobody-fused peptide antigens with a nanobody-STING agonist conjugate as an adjuvant. Following subcutaneous (SC) administration, albumin binding enhanced antigen and adjuvant transport to draining lymph nodes (LNs), promoting antigen cross-presentation and antigen-presenting cell (APC) activation that elicited robust antigen-specific CD8+ T cell responses. nAlb-Vax subsequently entered systemic circulation and preferentially accumulated within tumors, promoting an immunostimulatory TME that enhanced infiltration, proliferation, and function of vaccine-induced T cells. Therapeutic vaccination inhibited tumor growth and extended survival across multiple established murine solid tumor models, outperforming conventional vaccine technologies and generating durable immunity against multiple tumor-specific antigens (TSAs). These findings demonstrate that exploiting physiological albumin trafficking can coordinate lymphatic T cell priming with inflammatory TME remodeling to improve therapeutic cancer vaccination.