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

. doi: 10.1016/j.virs.2026.07.006

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

小分子PD-1/SHP-2抑制剂脓毒酸A（Pygenic Acid A）可提升黑色素瘤治疗性疫苗与流感预防性疫苗的免疫效力

闫妍 ^a ,
李怡桐 ^a ,
梅文义 ^b ,
李逸心 ^a ,
王茜 ^a ,
李洪林 ^b,, ,
陆路 ^a,, ,
姜世勃 ^a,,

a 复旦大学基础医学院, 上海市重大传染病和生物安全研究院;
b 华东师范大学药学院, 人工智能新药创智中心

通讯作者： 李洪林, hlli@hsc.ecnu.edu.cn; 陆路, lul@fudan.edu.cn; 姜世勃, shibojiang@fudan.edu.cn
收稿日期： 2026-06-03
录用日期： 2026-07-10

摘要

克服肿瘤微环境的免疫抑制特性是新型高端肿瘤疫苗研发的核心瓶颈。本研究聚焦PD-1/SHP-2信号轴，系统探究了胞内小分子抑制剂Pygenic Acid A（PA）作为新型疫苗佐剂的免疫增强效应与应用潜力。研究选取两种经典小鼠模型开展系统性验证：一是基于mTRP2抗原的治疗性B16-F10黑色素瘤肺转移模型，二是基于重组血凝素（HA）抗原的预防性H1N1流感病毒致死攻毒模型。在黑色素瘤肺转移模型中，PA可显著增强mTRP2疫苗的抗肿瘤疗效，有效抑制肺部转移灶的形成与进展，显著延长荷瘤小鼠生存期。机制研究证实，PA能够促进功能性T细胞向肿瘤组织浸润，有效逆转肿瘤局部的免疫抑制状态，重塑肿瘤微环境的免疫应答能力。在流感疫苗模型中，PA同样展现出优异的佐剂活性。经PA佐剂化的HA疫苗可高效诱导广谱交叉中和抗体应答，对致死剂量的H1N1流感病毒攻毒可为小鼠提供完全保护。深层机制分析表明，PA可特异性促进滤泡辅助性T细胞（Tfh）分化，推动引流淋巴结生发中心（GC）B细胞增殖扩增，同时诱导以IFN-γ分泌为核心的Th1型特异性细胞免疫应答，同步激活机体细胞免疫与体液免疫。体内安全性评价结果显示，PA介导的免疫干预不会引发明显的全身性炎症反应、血液学指标异常及内脏器官损伤，具备良好的生物安全性。综上，PA是一种高效、安全的胞内检查点靶向佐剂，可同步强化机体特异性细胞免疫与交叉保护性体液免疫，在新型抗肿瘤疫苗及广谱流感疫苗的研发领域具备重要的临床转化价值与应用前景。
- 疫苗佐剂
- , Pygenic Acid A
- , PD-1/SHP-2轴
- , 流感病毒
- , 黑色素瘤
- , 生发中心

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

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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