Haihong Zhang

DNA-based cancer vaccines represent a safe and promising immunotherapeutic strategy, but their clinical efficacy is often limited by weak immunogenicity, primarily due to inefficient antigen cross-presentation. To overcome this challenge, the MHC class I trafficking domain (MITD) can be fused to tumor antigens to enhance their intracellular routing in dendritic cells (DCs), thereby promoting the efficiency of cross-presentation. In addition, incorporation of CD4⁺ T cell epitopes, such as PADRE or P2P16, can robustly activate CD4⁺ T cells, further amplifying antitumor immunity. Thus, combining MITD with CD4⁺ epitopes is expected to synergistically improve DNA vaccine potency. Mesothelin (MSLN), a tumor-associated antigen highly expressed in pancreatic cancer, was selected as the target in this study. We designed MSLN-targeted DNA vaccines incorporating MITD together with either PADRE or P2P16. In a Panc02 murine model, the MITD–PADRE construct, a novel design, elicited stronger immune responses and more effective antitumor activity compared to other formulations. To further counteract immunosuppression, we combined the vaccine with gemcitabine, which enhanced therapeutic efficacy. Together, these findings demonstrate that integrating PADRE with MITD in MSLN-targeted DNA vaccines offers a promising combinatorial strategy for advancing pancreatic cancer immunotherapy.

DNA-based cancer vaccines represent a safe and promising immunotherapeutic strategy, but their clinical efficacy is often limited by weak immunogenicity, primarily due to inefficient antigen cross-presentation. To overcome this challenge, the MHC class I trafficking domain (MITD) can be fused to tumor antigens to enhance their intracellular routing in dendritic cells (DCs), thereby promoting the efficiency of cross-presentation. In addition, incorporation of CD4⁺ T cell epitopes, such as PADRE or P2P16, can robustly activate CD4⁺ T cells, further amplifying antitumor immunity. Thus, combining MITD with CD4⁺ epitopes is expected to synergistically improve DNA vaccine potency. Mesothelin (MSLN), a tumor-associated antigen highly expressed in pancreatic cancer, was selected as the target in this study. We designed MSLN-targeted DNA vaccines incorporating MITD together with either PADRE or P2P16. In a Panc02 murine model, the MITD–PADRE construct, a novel design, elicited stronger immune responses and more effective antitumor activity compared to other formulations. To further counteract immunosuppression, we combined the vaccine with gemcitabine, which enhanced therapeutic efficacy. Together, these findings demonstrate that integrating PADRE with MITD in MSLN-targeted DNA vaccines offers a promising combinatorial strategy for advancing pancreatic cancer immunotherapy.

Representative flow cytometry profiles (left) and statistical analysis (right) of MDSCs (Gr1+ CD11b+).

Mounting evidence suggests that immunotherapies are promising strategies for fighting against cancers. However, the immunosuppressive tumor microenvironment (TME), insufficient lymphocytic infiltration, and poor immunogenicity hamper the broader implementation of immunotherapies. LIGHT, a member of the TNF superfamily, has been shown to recruit T cells into the TME, turning “cold” tumors into “hot” ones. Here, a human mutant LIGHT (hmLIGHT) protein has been obtained which successfully promoted the activation and proliferation of mouse CD8+ T cells via CD28-independent co-stimulatory activity. Moreover, direct intratumoral injection of VR-hmLIGHT remodeled the TME, enhanced CD8+ T-cell infiltration into tumors, and showed antitumor efficacy in 4T1 and CT26 tumor models. In addition, our previous studies of a DNA vaccine (OsFS) have shown promising antitumor activity. In this study, we evaluated a new combination of VR-hmLIGHT and OsFS to enhance efficacy in the 4T1 tumor model. The combined treatment has a remarkable antitumor effect, with a tumor inhibition rate of 70%, whereas OsFS and VR-hmLIGHT groups displayed 32% and 42% inhibition, respectively. These findings indicate the clinical potential of LIGHT as monotherapy or combination therapy.

GO enrichment analysis of the cell components of DEGs between VR-MOCK and VR-hmLIGHT.

Amino acid sequence alignment of hmLIGHT and hLIGHT.

Representative flow cytometry profiles of CD25+FoxP3+ Treg cells in the spleen.

Flow cytometry gating strategy for Figure 3F.

The HIV-1 capsid has emerged as a highly attractive drug target due to its highly conserved sequence and critical role in the viral life cycle. By disrupting interactions between capsid proteins and impairing the proper assembly or disassembly of the capsid, the inhibitors can effectively suppress HIV-1 replication and infection. Based on this mechanism, numerous small-molecule agents targeting the HIV-1 capsid protein have been developed to date. In this review, we report the latest advances in such inhibitors and delve into their molecular mechanisms of action. We find a focus on small molecules modulating capsid stability and their assembly/disassembly. Hopefully this study will further enhance the understanding of HIV-1 inhibition mechanisms, facilitating the future exploration of novel capsid inhibitors.

Mounting evidence suggests that immunotherapies are promising strategies for fighting against cancers. However, the immunosuppressive tumor microenvironment (TME), insufficient lymphocytic infiltration, and poor immunogenicity hamper the broader implementation of immunotherapies. LIGHT, a member of the TNF superfamily, has been shown to recruit T cells into the TME, turning “cold” tumors into “hot” ones. Here, a human mutant LIGHT (hmLIGHT) protein has been obtained which successfully promoted the activation and proliferation of mouse CD8+ T cells via CD28-independent co-stimulatory activity. Moreover, direct intratumoral injection of VR-hmLIGHT remodeled the TME, enhanced CD8+ T-cell infiltration into tumors, and showed antitumor efficacy in 4T1 and CT26 tumor models. In addition, our previous studies of a DNA vaccine (OsFS) have shown promising antitumor activity. In this study, we evaluated a new combination of VR-hmLIGHT and OsFS to enhance efficacy in the 4T1 tumor model. The combined treatment has a remarkable antitumor effect, with a tumor inhibition rate of 70%, whereas OsFS and VR-hmLIGHT groups displayed 32% and 42% inhibition, respectively. These findings indicate the clinical potential of LIGHT as monotherapy or combination therapy.