Background While cancer vaccines have demonstrated promising clinical potential, their therapeutic efficacy against advanced tumors remains suboptimal, highlighting the critical need to elucidate resistance mechanisms and develop targeted solutions. We previously developed a stimulator of interferon genes (STING)-activating PC7A nanovaccine that elicits strong antitumor efficacy in multiple tumor models. In this study, we systematically investigated the mechanisms mediating nanovaccine resistance and provided targeting approaches to overcome this therapeutic barrier. Methods Vaccine efficacy at early stage and advanced-stage tumors was investigated in the B16-OVA melanoma model and TC-1 human papillomavirus-induced cancer model, with tumor microenvironment being comprehensively analyzed by flow cytometry. In a vaccine-resistant tumor, elevated immunosuppressive activity of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was assessed through multi-analysis including surface marker staining, reverse transcription-quantitative PCR, and functional T cell-suppression assay. To investigate the CD300ld blockade strategy, we employed CD300ld-knockout (KO) mice for genetic ablation, or recombinant protein capable of competitive inhibition for pharmacological intervention. For clinical relevance assessment, we tested different cancer vaccine formulations at late-stage tumors in humanized-CD3000ld mice. Results In contrast to early stage vaccination, PC7A nanovaccine administration at the late tumor stage exhibited minimal therapeutic effects on tumor progression, while concurrently increasing PMN-MDSC infiltration and enhancing their immunosuppressive activity. KO of CD300ld, a critical immune suppressor on PMN-MDSCs, abolished both PMN-MDSC recruitment and their T-cell suppressive function, restoring the antitumor efficacy of PC7A vaccine in multiple advanced tumor models. Furthermore, in wild-type and CD300ld humanized mouse models, competitive blockade of CD300ld using recombinant extracellular domain proteins overcame resistance of advanced tumors to different cancer vaccine formulations. Conclusion Our results reveal that vaccination at the late tumor stage significantly augments the recruitment and immunosuppressive capacity of PMN-MDSCs, driving resistance of advanced tumors to cancer vaccines. The findings demonstrate PMN-MDSCs as critical mediators of vaccine resistance in advanced tumors and highlight modulation of PMN-MDSCs by CD300ld blockade as a promising strategy to enhance the therapeutic efficacy of cancer vaccines, particularly for patients with late-stage malignancies.
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