Monophosphoryl lipid A-assembled nanovaccines enhance tumor immunotherapy

Therapeutic cancer nanovaccines can induce strong antitumor immunity and establish long-term immune memory and have shown potential for curing tumors in some clinical trials. However, weak immunogenicity and safety concerns of nanocarriers limit the clinical translation of some therapeutic nanovaccines. Here, we developed minimal-component cancer nanovaccines, monophosphoryl lipid A (MPLA)-assembled nanovaccines (MANs), that could facilitate the clinical application of nanovaccines. The MANs were formed by protein antigens extracted from chemotherapy-induced tumor cell cultures and the amphiphilic immune adjuvant MPLA. Compared with free chemotherapy-induced antigens, MANs can activate the Toll-like receptor 4 (TLR4)-mediated signalling pathway and promote adaptive immunity against tumor antigens. Mechanistic analysis indicated that MANs induced antigen capture of DCs and promoted the activation of DCs and T cells, thereby optimizing the ratio of CD8⁺ T/Tregs in tumors and facilitating the transformation of the tumor immune microenvironment (TIME) from "cold" to "hot". In a CT26 colorectal cancer model, MANs+αPD-1 significantly improved the efficacy of αPD-1 treatment. Our work offers a strategy for designing minimal-component cancer nanovaccines with potential clinical benefits. STATEMENT OF SIGNIFICANCE: To address the weak immunogenicity of cancer vaccines and the safety concerns of nanocarriers, we prepared MPLA-assembled nanovaccines (MANs) using chemotherapy induced antigens and the immune adjuvant MPLA to promote cancer vaccines to clinical practice. MANs effectively internalized tumor antigens and induced DC maturation, indicating that the initial anti-tumor response had been activated. MANs+αPD-1 induced APCs, CD8⁺ T cells and memory T cells with positive anti-tumor effects to migrate to tumor tissue, thus leading to the transformation of the tumor immune microenvironment from "cold" to "hot". At the animal level, the combination of MANs and αPD-1 exerted synergistic effects and significantly enhanced tumor immunotherapy. Therefore, the treatment regimen of MANs+αPD-1 has potential clinical benefits.