Calreticulin Enhances Therapeutic Immune Responses of Dry Thermostat-Stressed Hepatocellular Carcinoma Cell Vaccine

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Despite the promise of whole tumor cell vaccines in personalized cancer immunotherapy, their limited immunogenicity and lack of danger signals hinder their clinical efficacy. Herein, we introduce a time-efficient (within 2 h) dry thermostat (DT) device-based method to prepare CpG RTC-vax 100, a therapeutic vaccine generated by treating tumor cells through DT and further decorated with cholesterol-linked CpG-ODNs, to eliminate orthotopic hepatocellular carcinoma (HCC). The DT treatment preserves tumor cell morphology integrity and antigenic activity, promotes the translocation of calreticulin to the cell surface (approximately 13-fold), upregulates HSP70 (around 3.4-fold), and induces DNA breaks while immediately inactivating tumor cells within 5 min. This approach overcomes the limitations of existing whole cell vaccines by enhancing immunogenicity and exposing pathogen-associated and damage-associated molecular patterns. These changes led to efficient tumor antigen uptake, dendritic cell activation, and increased levels of CXCL-10, Gzms-B, IL-6, and IL-12 in tumors. Consequently, the T-cell infiltration into orthotopic HCC is enhanced. Mechanistic studies reveal that NK cells, CD4 + T cells, and activated CD8 + T cells are recruited, alongside with reduced Tregs within the tumor. Furthermore, CpG RTC-vax 100 activates patient-derived DC-T cells, demonstrating an efficient antitumor effect in patient-derived xenograft models through adoptive transfer of activated DC-T cells. Our findings highlight the potential of physical methods in enhancing tumor cell vaccine immunogenicity and their therapeutic promise for addressing the urgent needs of HCC treatment.

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