SHP2抑制类药物的开发及在肿瘤治疗中的应用研究进展

doi:10.3969/j.issn.1674-8115.2026.06.003

摘要/Abstract

摘要：

由PTPN11基因编码的含Src同源2结构域蛋白酪氨酸磷酸酶2（Src homology 2 domain-containing protein tyrosine phosphatase 2，SHP2）是非受体型蛋白酪氨酸磷酸酶（protein tyrosine phosphatase，PTP）家族中的重要分子，可调控包括RAS/丝裂原活化蛋白激酶（RAS/mitogen-activated protein kinase，RAS/MAPK）、磷脂酰肌醇3-激酶/蛋白激酶B（phosphoinositide 3-kinase/protein kinase B，PI3K/AKT）、Janus激酶/信号转导与转录激活因子（Janus kinase/signal transducer and activator of transcription，JAK/STAT）、程序性死亡受体1/程序性死亡配体1（programmed cell death 1/programmed cell death ligand 1，PD-1/PD-L1）在内的多条核心信号通路，影响肿瘤细胞的增殖、分化、存活与凋亡，并在介导肿瘤耐药中发挥重要作用。在肿瘤微环境（tumor microenvironment，TME）中，SHP2扮演着关键的免疫抑制调节角色，即能够通过参与免疫检查点下游信号转导，抑制T细胞的活化和效应功能，同时调控巨噬细胞等免疫细胞的状态，促进肿瘤免疫逃逸。鉴于SHP2在驱动肿瘤生长和介导免疫抑制中的双重作用，靶向SHP2治疗已成为极具前景的抗肿瘤策略。SHP2抑制剂不仅能抑制致癌信号通路，更能有效解除SHP2对T细胞的抑制、重塑免疫微环境，从而产生协同抗肿瘤效应。同时，SHP2抑制剂与现有疗法的联合应用也展现出了克服耐药、提升疗效的巨大潜力，是当前肿瘤治疗研究的重要方向。基于此，该文总结了SHP2的生物学功能、相关信号网络、在肿瘤发生与免疫逃逸中的作用机制，分析了SHP2相关药物开发的进展以及联合治疗策略的应用前景，以期为解决肿瘤治疗问题提供新的思路和方向。

关键词: 含Src同源2结构域蛋白酪氨酸磷酸酶2, 肿瘤微环境, 免疫治疗

Abstract:

Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is an important molecule in the non-receptor protein tyrosine phosphatase (PTP) family. It can regulate multiple core signaling pathways, including RAS/mitogen-activated protein kinase (RAS/MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1). SHP2 affects the proliferation, differentiation, survival, and apoptosis of tumor cells, and plays an important role in mediating tumor drug resistance. In the tumor microenvironment (TME), SHP2 plays a key role in the regulation of immunosuppression. It can inhibit the activation and effector functions of T cells by participating in the downstream signal transduction of immune checkpoints, while also regulating the status of immune cells such as macrophages and promoting tumor immune escape. Given the dual roles of SHP2 in driving tumor growth and mediating immunosuppression, SHP2-targeted therapy has become a promising anti-tumor strategy. SHP2 inhibitors can not only inhibit the carcinogenic signaling pathways, but also effectively relieve the inhibition of SHP2 on T cells and reprogram the immune microenvironment, thus producing synergistic anti-tumor effects. At the same time, the combined application of SHP2 inhibitors with existing therapies also shows great potential in overcoming drug resistance and improving efficacy, which is an important direction in current tumor treatment research. Based on this, this review summarizes the biological functions and related signaling networks of SHP2, as well as its mechanisms in tumorigenesis and immune escape, and analyzes the research progress of SHP2-targeted drug development and the application prospects of combination treatment strategies, in order to provide new ideas and references for tumor treatment research.

Key words: Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), tumor microenvironment (TME), immunotherapy

中图分类号:

R915

沈雨潇, 李晓光, 巴乾. SHP2抑制类药物的开发及在肿瘤治疗中的应用研究进展[J]. 上海交通大学学报（医学版）, 2026, 46(6): 713-720.

Shen Yuxiao, Li Xiaoguang, Ba Qian. Research progress in development of SHP2 inhibitors and their application in tumor therapy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(6): 713-720.

图/表 3

图 1 SHP2调控肿瘤细胞和免疫细胞的相关信号通路Note： RTKs—receptor tyrosine kinases; GRB2(Grb2)—growth factor receptor-bound protein 2; SOS1—son of sevenless homolog 1; SPRY—Sprouty homolog; GAB1—GRB2-associated binding protein 1; RasGAP—Ras GTPase-activating protein; RAS-GDP—Rat sarcoma guanosine diphosphate; RAS-GTP—Rat sarcoma guanosine triphosphate; Raf—rapidly accelerated fibrosarcoma; MEK—mitogen-activated protein ERK kinase; ERK—extracellular signal-regulated kinase; PI3K—phosphatidylinositol 3-kinase; AKT—protein kinase B; mTOR — mechanistic target of rapamycin; JAK—Janus kinase; STAT3—signal transducer and activator of transcription 3; MHC—major histocompatibility complex; TCR—T cell receptor; ZAP70—zeta-chain-associated protein kinase 70; PD-L1—programmed cell death ligand 1; PD-1—programmed cell death 1; ITIM—immunoreceptor tyrosine-based inhibitory motif; ITSM—immunoreceptor tyrosine-based switch motif; CD28—cluster of differentiation 28; CTLA-4—cytotoxic T-lymphocyte-associated antigen 4; Siglec-10—sialic acid-binding immunoglobulin-like lectin 10; SIRPα—signal regulatory protein α; CSF-1—colony-stimulating factor 1; CSF-1R—colony-stimulating factor 1 receptor.

Fig 1 SHP2-regulated signaling pathways in tumor cells and immune cells

图 2 SHP2抑制类药物的作用机制Note： A. Mechanism of catalytic-site inhibitors. B. Mechanism of allosteric inhibitors. C. Mechanism of SHP2-PROTAC drugs. D. Mechanism of PD-1-SHP2 interaction inhibitors. PHPS1—phenylhydrazonopyrazolone sulfonate 1; IC50 —half maximal inhibitory concentration.

Fig 2 Mechanisms of action of SHP2 inhibitors

表1 SHP2变构抑制剂的临床试验概况

Tab 1 Overview of clinical trials of SHP2 allosteric inhibitors

Compound	NCT number	Planned enrollment/n	Phase	Start date	Status	Indication
TNO155	NCT03114319	227	Ⅰ	2018/09/14	Not yet recruiting	Advanced non-small cell lung cancer, esophageal squamous cell carcinoma, melanoma
JAB-3068	NCT03518554	38	Ⅰ	2018/04/23	Not yet recruiting	Esophageal cancer, head and neck cancer, non-small cell lung cancer, metastatic solid tumor
JAB-3068	NCT03565003	126	Ⅰ/Ⅱ	2018/05/29	Not yet recruiting
RMC-4630	NCT03634982	133	Ⅰ	2018/09/28	Active, not recruiting	Solid tumor
JAB-3312	NCT04045496	24	Ⅰ	2019/09/26	Recruiting	Small cell lung cancer, colorectal cancer, pancreatic ductal carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, breast cancer
JAB-3312	NCT04121286	17	Ⅰ	2020/07/14	Not yet recruiting
BBP-398	NCT04528836	72	Ⅰ	2020/11/12	Terminated	Advanced solid tumor, advanced or metastatic non-small cell lung cancer
BBP-398	NCT05621525	7	Ⅰ	2022/10/18	Terminated
PF07284892	NCT04800822	53	Ⅰ	2021/03/17	Terminated	Solid tumor
SH-3809	NCT04843033	55	Ⅰ	2021/04/02	Recruiting	Solid tumor
ERAS-601	NCT04670679	200	Ⅰ	2020/12/15	Active, not recruiting	Advanced or metastatic non-small cell lung cancer
HBI-2376	NCT05163028	42	Ⅰ	2021/12/13	Active, not recruiting	Colorectal cancer, pancreatic cancer, non-small cell lung cancer, solid tumor
BPI-442096	NCT05369312	230	Ⅰ	2022/06	Not yet recruiting	Colorectal cancer, non-small cell lung cancer, pancreatic cancer, solid tumor
HS-10381	NCT05378178	51	Ⅰ	2022/06/08	Recruiting	Solid tumor
HMPL-415S1	NCT05886374	81	Ⅰ	2023/07/06	Recruiting	Solid tumor

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