Shih-Jen Liu

Lung cancer‐mediated myeloid‐derived suppressor cell (MDSC) inhibits antitumour immunity for tumour progression and is a promising target. Here, we present the ADAM9‐targeting therapeutic strategy to unleash anticancer immunity. We identified a novel role for ADAM9 in promoting lung cancer immunosuppression through the upregulation of cytokines that drive the recruitment and expansion of MDSCs, with CXCL12 serving as one of the major mediators. This ADAM9–CXCL12–MDSC axis significantly impairs the function of cytotoxic CD8+ T cells. Disrupting the ADAM9–CXCL12 axis suppresses oncogenic signalling pathways, including EGFR and IL‐6 signalling. Therapeutically, the developed ADAM9 inhibitors significantly reduced primary tumour growth and metastasis in syngeneic mouse models of lung tumours, concurrent with remodelling of the immune microenvironment. This study demonstrates that ADAM9 promotes cancer‐mediated MDSC function by enhancing CXCL12 production. Targeting ADAM9 represents a novel and effective strategy to reverse the immunosuppressive tumour microenvironment and suppress lung cancer progression.

DNA vaccines offer advantages such as low production cost, rapid manufacturing, and enhanced stability for transport and storage, making them suitable for addressing tropical and emerging infectious diseases. However, their limited immunogenicity in humans often necessitates multiple booster doses or high antigen quantities, posing a significant barrier to broader application. To overcome this limitation, we developed a DNA vaccine encoding the Zika virus (ZIKV) structural proteins (prME) that incorporates a non‐targeting short hairpin RNA (shRNA) as an intrinsic molecular adjuvant. This shRNA is not designed to silence host genes; rather, it enhances innate immune “RIG‐I” signaling by selectively activating the IRE1α‐dependent regulated IRE1‐dependent decay pathway. Mechanistically, shRNA overexpression is inferred to increase the load on the RNA‐induced silencing complex, potentially triggering IRE1α oligomerization and subsequent upregulation of TXNIP. These events generate cytoplasmic RNA fragments that activate RIG‐I and downstream antiviral responses. In murine models, the vaccine elicited strong ZIKV‐specific humoral and cellular immune responses. In AGB6 mice, it significantly increased neutralizing antibody titers, reduced viremia, and improved survival. This approach enhances the immunogenicity of DNA vaccines without targeting host genes, providing a scalable and adaptable platform for infectious disease prevention.

Nucleic acid vaccines have emerged as crucial advancements in vaccine technology, particularly highlighted by the global response to the COVID-19 pandemic. The widespread administration of mRNA vaccines against COVID-19 to billions globally marks a significant milestone. Furthermore, the approval of an mRNA vaccine for Respiratory Syncytial Virus (RSV) this year underscores the versatility of this technology. In oncology, the combination of mRNA vaccine encoding neoantigens and immune checkpoint inhibitors (ICIs) has shown remarkable efficacy in eliciting protective responses against diseases like melanoma and pancreatic cancer. Although the use of a COVID-19 DNA vaccine has been limited to India, the inherent stability at room temperature and cost-effectiveness of DNA vaccines present a viable option that could benefit developing countries. These advantages may help DNA vaccines address some of the challenges associated with mRNA vaccines. Currently, several trials are exploring the use of DNA-encoded neoantigens in combination with ICIs across various cancer types. These studies highlight the promising role of nucleic acid-based vaccines as the next generation of immunotherapeutic agents in cancer treatment. This review will delve into the recent advancements and current developmental status of both mRNA and DNA-based cancer vaccines.

Pneumococcal disease is a major threat to public health globally, impacting individuals across all age groups, particularly infants and elderly individuals. The use of current vaccines has led to unintended consequences, including serotype replacement, leading to a need for a new approach to combat pneumococcal disease. A promising solution is the development of a broad-spectrum pneumococcal vaccine. In this study, we present the development of a broad-spectrum protein-based pneumococcal vaccine that contains three pneumococcal virulence factors: rlipo-PsaA (lipidated form), rPspAΔC (truncated form), and rPspCΔC (truncated form). Intranasal immunization with rlipo-PsaA, rPspAΔC, and rPspCΔC (LAAC) resulted in significantly higher IgG titres than those induced by administration of nonlipidated rPsaA, rPspAΔC, and rPspCΔC (AAC). Furthermore, LAAC immunization induced the production of higher IgA titres in vaginal washes, feces, and sera in mice, indicating that LAAC can induce systemic mucosal immunity. In addition, administration of LAAC also induced Th1/Th17-biased immune responses and promoted opsonic phagocytosis of Streptococcus pneumoniae strains of various serotypes, implying that the immunogenicity of LAAC immunization provides a protective effect against pneumococcal infection. Importantly, challenge data showed that the LAAC-immunized mice had a reduced bacterial load not only for several serotypes of the 13-valent conjugate pneumococcal vaccine (PCV13) but also for selected non-PCV13 serotypes. Consistently, LAAC immunization increased the survival rate of mice after bacterial challenge with both PCV13 and non-PCV13 serotypes. In conclusion, our protein-based pneumococcal vaccine provides protective effects against a broad spectrum of Streptococcus pneumoniae serotypes.

Antigen sparing is an important strategy for pandemic vaccine development because of the limitation of worldwide vaccine production during disease outbreaks. However, several clinical studies have demonstrated that the current aluminum (Alum)-adjuvanted influenza vaccines fail to sufficiently enhance immune responses to meet licensing criteria. Here, we used pandemic H7N9 as a model virus to demonstrate that a 10-fold lower amount of vaccine antigen combined with Alum and TLR9 agonist can provide stronger protective effects than using Alum as the sole adjuvant. We found that the Alum/CpG 1018 combination adjuvant could induce more robust virus-specific humoral immune responses, including higher total IgG production, hemagglutination-inhibiting antibody activity, and neutralizing antibody titres, than the Alum-adjuvanted formulation. Moreover, this combination adjuvant shifted the immune response toward a Th1-biased immune response. Importantly, the Alum/CpG 1018-formulated vaccine could confer better protective immunity against H7N9 challenge than that adjuvanted with Alum alone. Notably, the addition of CpG 1018 to the Alum-adjuvanted H7N9 whole-virion vaccine exhibited an antigen-sparing effect without compromising vaccine efficacy. These findings have significant implications for improving Alum-adjuvanted influenza vaccines using the approved adjuvant CpG 1018 for pandemic preparedness.

Formyl peptide receptor-like 1 inhibitor protein (FLIPr) is an immune evasion protein produced by Staphylococcus aureus, and FLIPr is a potential vaccine candidate for reducing Staphylococcus aureus virulence and biofilm formation. We produced recombinant lipidated FLIPr (rLF) to increase the immunogenicity of FLIPr and showed that rLF alone elicited potent anti-FLIPr antibody responses to overcome the FLIPr-mediated inhibition of phagocytosis. In addition, rLF has potent immunostimulatory properties. We demonstrated that rLF is an effective adjuvant. When an antigen is formulated with rLF, it can induce long-lasting antigen-specific immune responses and enhance mucosal and systemic antibody responses as well as broad-spectrum T-cell responses in mice. These findings support further exploration of rLF in the clinic as an adjuvant for various vaccine types with extra benefits to abolish FLIPr-mediated immunosuppressive effects.