Effect of a promising autologous therapeutic cancer nanovaccine on tumor associated macrophages for augmented lung cancer immunotherapy.

e14641 Background: Autologous cancer vaccines hold significant promise in personalized cancer immunotherapy; however, their clinical application is hindered by challenges such as tumor heterogeneity, low antigen utilization efficiency, and the immunosuppressive tumor microenvironment. The key challenge in developing personalized cancer vaccines lies in how to generate and adsorb autologous antigens in vivo , actively target immune cells, and adequately stimulate immune cells. Designing novel cancer vaccines based on the tumor destruction and antigen presentation functions of tumor-associated macrophages following M1 polarization could address these issues. Methods: APS@PLGA (AP) nanoparticles were synthesized via double-emulsion and modified with NH 2 -PEG-Man to create mannosylated APS@PLGA (APM). Particle size, structure, encapsulation efficiency, and drug release at different pH were evaluated. Proteomics and BCA assays assessed antigen adsorption. Cytotoxicity, macrophage uptake, and in vivo effects on LLC tumor-bearing mice (body weight, tumor volume, survival) were studied. Immune response was evaluated using flow cytometry, ELISA, ELISpot, immunohistochemistry, and 5'RACE-TCR sequencing. PANoptosis was measured by Western blot/qPCR, and transcriptomics revealed related pathways and biomarkers. Targeting and biodistribution were analyzed by imaging, with biosafety assessed by histology and biochemical tests. Results: APM particles (145 ± 1.53 nm, -17.17 ± 0.84 mV) encapsulated 77.81 ± 0.01% polysaccharides and showed pH-responsive release with high antigen adsorption (664.293 ± 1.513 mg/mg). No macrophage toxicity was observed at 500 μg/mL. APM increased macrophage proliferation, antigen uptake, and polarized macrophages toward M1. In vivo , APM and APM+αPD-L1 reduced tumor volumes (9.03 and 22 times vs control) and improved survival. Flow cytometry showed increased M1 macrophages, Th1 and CD8+ T cells, and PANoptosis activation was confirmed by transcriptomic analysis, western blot and qPCR. Imaging and biosafety tests indicated favorable outcomes. Conclusions: Overall, this study demonstrates that APM, as an autologous tumor vaccine, can significantly enhance tumor cell killing and antigen presentation, thereby strengthening the body's anti-tumor immune response. It offers several advantages, including high biological safety, significant anti-tumor efficacy, a simple preparation process, and low cost, making it particularly suitable for widespread clinical application. APM also exhibited a strong synergistic effect with PD-L1 inhibitors in vivo experiments. This research offers additional therapeutic options for lung cancer and potentially other types of cancer, further promoting the personalized and precise development of cancer immunotherapy.