Pygenic acid A, a small-molecule PD-1/SHP-2 inhibitor, enhances efficacy of therapeutic melanoma vaccines and prophylactic influenza vaccines

Yan Yan; Yitong Li; Wenyi Mei; Yixin Li; Qian Wang; Honglin Li; Lu Lu; Shibo Jiang

doi:10.1016/j.virs.2026.07.006

August 2026

Citation: Yan Yan, Yitong Li, Wenyi Mei, Yixin Li, Qian Wang, Honglin Li, Lu Lu, Shibo Jiang. Pygenic acid A, a small-molecule PD-1/SHP-2 inhibitor, enhances efficacy of therapeutic melanoma vaccines and prophylactic influenza vaccines .VIROLOGICA SINICA, 2026, 41(4) : 961-971. http://dx.doi.org/10.1016/j.virs.2026.07.006

Pygenic acid A, a small-molecule PD-1/SHP-2 inhibitor, enhances efficacy of therapeutic melanoma vaccines and prophylactic influenza vaccines

Yan Yan ^a ,
Yitong Li ^a ,
Wenyi Mei ^b ,
Yixin Li ^a ,
Qian Wang ^a ,
Honglin Li ^{b
,,} ,
Lu Lu ^{a
,,} ,
Shibo Jiang ^{a
,,}

a. Key Laboratory of Medical Molecular Virology (Ministry of Education/National Health Commission/Chinese Academy of Medical Science), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;
b. Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai 200062, China

Corresponding author: Honglin Li, hlli@hsc.ecnu.edu.cn
Lu Lu, lul@fudan.edu.cn
Shibo Jiang, shibojiang@fudan.edu.cn
Received Date: 03 June 2026
Accepted Date: 10 July 2026
Available online: 16 July 2026

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.
- Vaccine adjuvant
- , Pygenic acid A (PA)
- , PD-1/SHP-2 axis
- , Influenza virus
- , Melanoma
- , Germinal center

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