Effects of SHP2 inhibition on macrophage-related inflammatory factors in <i>KRAS</i>-mutant lung cancer cells_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZENG Penghui ,  ZHANG Xuchao

Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, P. R. China;

Corresponding author：

ZHANG Xuchao, Email: zhxuchao3000@126.com

Keywords：

SHP2; KRAS-mutant lung cancer; macrophage; inflammatory factor

DOI：

10.7507/1007-4848.202503031

Video：

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Objective To investigate the regulatory effects of SHP2 inhibition on the secretion of macrophage-associated inflammatory factors in KRAS-mutant lung cancer cells and to elucidate the underlying mechanisms by which this inhibition remodels the tumor immune microenvironment. Methods Three KRAS-mutant lung cancer cell lines were treated with the SHP2 inhibitor SHP099. The levels of phosphorylated SHP2 and ERK were assessed by Western blot. The expression levels of related inflammatory factors were analyzed using Luminex assay and qRT-PCR assay. Transcriptome sequencing was performed to identify differentially expressed genes and conduct KEGG pathway enrichment analysis. The expression of CXCL8 was validated by flow cytometry and Western blot. Survival analysis and gene set correlation analysis were conducted based on the TCGA database. Results SHP099 significantly inhibited the expression of p-SHP2 and p-ERK proteins, and reduced the secretion of multiple macrophage-related inflammatory factors. qRT-PCR confirmed a decrease in CXCL8 mRNA levels. Transcriptome analysis revealed significant enrichment of the rheumatoid arthritis pathway. Flow cytometry and Western blot validated a significant reduction in CXCL8 protein expression. Survival analysis showed that patients with KRAS-mutant lung adenocarcinoma and high CXCL8 expression had a shorter overall survival, and CXCL8 was positively correlated with M2 macrophage marker genes. Conclusion Targeted inhibition of SHP2 can suppress the expression of some macrophage-related inflammatory factors in KRAS-mutant lung cancer cells, with the most significant inhibition of CXCL8 expression. The mechanism may involve SHP2 regulating the transcription factor AP-1.

1.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2.	Vicidomini G. Current challenges and future advances in lung cancer: Genetics, instrumental diagnosis and treatment. Cancers (Basel), 2023, 15(14): 3710.
3.	Karimi N, Moghaddam SJ. KRAS-mutant lung cancer: Targeting molecular and immunologic pathways, therapeutic advantages and restrictions. Cells, 2023, 12(5): 749.
4.	Asmamaw MD, Shi XJ, Zhang LR, et al. A comprehensive review of SHP2 and its role in cancer. Cell Oncol (Dordr), 2022, 45(5): 729-753.
5.	Chen YN, LaMarche MJ, Chan HM, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature, 2016, 535(7610): 148-152.
6.	Hao HX, Wang H, Liu C, et al. Tumor intrinsic efficacy by SHP2 and RTK inhibitors in KRAS-mutant cancers. Mol Cancer Ther, 2019, 18(12): 2368-2380.
7.	Prahallad A, Weiss A, Voshol H, et al. CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer. Cancer Res, 2023, 83(24): 4130-4141.
8.	Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med, 2021, 218(1): e20201414.
9.	Christofides A, Katopodi XL, Cao C, et al. SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses. Nat Immunol, 2023, 24(1): 55-68.
10.	Christofides A, Strauss L, Yeo A, et al. The complex role of tumor-infiltrating macrophages. Nat Immunol, 2022, 23(8): 1148-1156.
11.	Tang KH, Li S, Khodadadi-Jamayran A, et al. Combined inhibition of SHP2 and CXCR1/2 promotes antitumor T-cell response in NSCLC. Cancer Discov, 2022, 12(1): 47-61.
12.	Habanjar O, Bingula R, Decombat C, et al. Crosstalk of inflammatory cytokines within the breast tumor microenvironment. Int J Mol Sci, 2023, 24(4): 4002.
13.	Martínez-Sabadell A, Arenas EJ, Arribas J. IFNγ signaling in natural and therapy-induced antitumor responses. Clin Cancer Res, 2022, 28(7): 1243-1249.
14.	Sun Y, Wang Q, Jiang Y, et al. Lactobacillus intestinalis facilitates tumor-derived CCL5 to recruit dendritic cell and suppress colorectal tumorigenesis. Gut Microbes, 2025, 17(1): 2449111.
15.	Li L, Hao S, Gao M, et al. HDAC3 inhibition promotes antitumor immunity by enhancing CXCL10-mediated chemotaxis and recruiting of immune cells. Cancer Immunol Res, 2023, 11(5): 657-673.
16.	Shiri AM, Zhang T, Bedke T, et al. IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J Hepatol, 2024, 80(4): 634-644.
17.	Perez-Penco M, Byrdal M, Lara de la Torre L, et al. The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling. Cell Mol Immunol, 2025, 22(1): 111-126.
18.	Wang S, Liu G, Li Y, et al. Metabolic reprogramming induces macrophage polarization in the tumor microenvironment. Front Immunol, 2022, 13: 840029.
19.	Shao Y, Lan Y, Chai X, et al. CXCL8 induces M2 macrophage polarization and inhibits CD8+ T cell infiltration to generate an immunosuppressive microenvironment in colorectal cancer. FASEB J, 2023, 37(10): e23173.
20.	Xiong X, Liao X, Qiu S, et al. CXCL8 in tumor biology and its implications for clinical translation. Front Mol Biosci, 2022, 9: 723846.
21.	Han X, Wei J, Zheng R, et al. Macrophage SHP2 deficiency alleviates diabetic nephropathy via suppression of MAPK/NF-κB-dependent inflammation. Diabetes, 2024, 73(5): 780-796.
22.	Sheng Y, Lin Y, Qiang Z, et al. Protein kinase A suppresses antiproliferative effect of interferon-α in hepatocellular carcinoma by activation of protein tyrosine phosphatase SHP2. J Biol Chem, 2025, 301(2): 108195.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Vicidomini G. Current challenges and future advances in lung cancer: Genetics, instrumental diagnosis and treatment. Cancers (Basel), 2023, 15(14): 3710.
3. Karimi N, Moghaddam SJ. KRAS-mutant lung cancer: Targeting molecular and immunologic pathways, therapeutic advantages and restrictions. Cells, 2023, 12(5): 749.
4. Asmamaw MD, Shi XJ, Zhang LR, et al. A comprehensive review of SHP2 and its role in cancer. Cell Oncol (Dordr), 2022, 45(5): 729-753.
5. Chen YN, LaMarche MJ, Chan HM, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature, 2016, 535(7610): 148-152.
6. Hao HX, Wang H, Liu C, et al. Tumor intrinsic efficacy by SHP2 and RTK inhibitors in KRAS-mutant cancers. Mol Cancer Ther, 2019, 18(12): 2368-2380.
7. Prahallad A, Weiss A, Voshol H, et al. CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer. Cancer Res, 2023, 83(24): 4130-4141.
8. Fedele C, Li S, Teng KW, et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med, 2021, 218(1): e20201414.
9. Christofides A, Katopodi XL, Cao C, et al. SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses. Nat Immunol, 2023, 24(1): 55-68.
10. Christofides A, Strauss L, Yeo A, et al. The complex role of tumor-infiltrating macrophages. Nat Immunol, 2022, 23(8): 1148-1156.
11. Tang KH, Li S, Khodadadi-Jamayran A, et al. Combined inhibition of SHP2 and CXCR1/2 promotes antitumor T-cell response in NSCLC. Cancer Discov, 2022, 12(1): 47-61.
12. Habanjar O, Bingula R, Decombat C, et al. Crosstalk of inflammatory cytokines within the breast tumor microenvironment. Int J Mol Sci, 2023, 24(4): 4002.
13. Martínez-Sabadell A, Arenas EJ, Arribas J. IFNγ signaling in natural and therapy-induced antitumor responses. Clin Cancer Res, 2022, 28(7): 1243-1249.
14. Sun Y, Wang Q, Jiang Y, et al. Lactobacillus intestinalis facilitates tumor-derived CCL5 to recruit dendritic cell and suppress colorectal tumorigenesis. Gut Microbes, 2025, 17(1): 2449111.
15. Li L, Hao S, Gao M, et al. HDAC3 inhibition promotes antitumor immunity by enhancing CXCL10-mediated chemotaxis and recruiting of immune cells. Cancer Immunol Res, 2023, 11(5): 657-673.
16. Shiri AM, Zhang T, Bedke T, et al. IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J Hepatol, 2024, 80(4): 634-644.
17. Perez-Penco M, Byrdal M, Lara de la Torre L, et al. The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling. Cell Mol Immunol, 2025, 22(1): 111-126.
18. Wang S, Liu G, Li Y, et al. Metabolic reprogramming induces macrophage polarization in the tumor microenvironment. Front Immunol, 2022, 13: 840029.
19. Shao Y, Lan Y, Chai X, et al. CXCL8 induces M2 macrophage polarization and inhibits CD8+ T cell infiltration to generate an immunosuppressive microenvironment in colorectal cancer. FASEB J, 2023, 37(10): e23173.
20. Xiong X, Liao X, Qiu S, et al. CXCL8 in tumor biology and its implications for clinical translation. Front Mol Biosci, 2022, 9: 723846.
21. Han X, Wei J, Zheng R, et al. Macrophage SHP2 deficiency alleviates diabetic nephropathy via suppression of MAPK/NF-κB-dependent inflammation. Diabetes, 2024, 73(5): 780-796.
22. Sheng Y, Lin Y, Qiang Z, et al. Protein kinase A suppresses antiproliferative effect of interferon-α in hepatocellular carcinoma by activation of protein tyrosine phosphatase SHP2. J Biol Chem, 2025, 301(2): 108195.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

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