ArticleVirologica Sinica2026
Pygenic acid A, a small-molecule PD-1/SHP-2 inhibitor, enhances efficacy of therapeutic melanoma vaccines and prophylactic influenza vaccines.
Article in Virologica Sinica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Overcoming immunosuppressive tumor microenvironments remains a critical challenge in advanced vaccine development. Here, we evaluated Pygenic acid A (PA), an intracellular small-molecule inhibitor targeting the PD-1/SHP-2 axis, as a novel vaccine adjuvant. The adjuvant efficacy of PA was systematically assessed in two murine models: a therapeutic B16-F10 melanoma lung metastasis model and a prophylactic lethal H1N1 influenza virus challenge model. In the melanoma metastasis model, PA potentiated the anti-tumor effect of the mTRP2 vaccine, markedly inhibiting pulmonary metastatic lesions and prolonging the survival of tumor-bearing mice. Mechanistically, PA robustly boosted the intratumoral infiltration of functional T cells, thereby reversing local tumor immunosuppression. In the influenza vaccination model, consistent immunostimulatory effects were observed: the PA-adjuvanted hemagglutinin (HA) vaccine effectively elicited broad-spectrum cross-neutralizing antibody responses and provided complete protection against lethal heterologous influenza virus challenge. Further mechanistic investigations demonstrated that PA specifically promoted the differentiation of T follicular helper (Tfh) cells and the expansion of germinal center (GC) B cells in draining lymph nodes, while triggering a robust Th1-type cellular immune response dominated by IFN-γ secretion. Furthermore, in vivo safety assessments verified that PA intervention induced no obvious systemic inflammation, hematological abnormalities, or visceral organ injury, indicating a favorable safety profile. Collectively, these results demonstrate that PA serves as a potent and safe intracellular checkpoint-targeting adjuvant capable of potentiating both cellular immunity and cross-protective humoral immunity, holding great translational promise for the development of advanced cancer vaccines and broad-spectrum influenza vaccines.
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