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IL-22 confers EGFR-TKI resistance in colorectal cancer by modulating ROS/STAT3/SHP2/Src signals
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DOI：10.1186/s40001-026-05017-0.png)
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Abstract
En 中文
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are central to colorectal cancer (CRC) therapy, but acquired resistance limits their efficacy. This study investigates whether interleukin-22 (IL-22) mediates this resistance and explores the underlying mechanisms. Single-cell transcriptomics compared cell subsets, stemness, and cell–cell communication in CRC samples before and after gefitinib resistance acquisition, with bioinformatics guiding mechanistic experiments. SW480 and HCT8 cells were treated with EGF, gefitinib, IL-22, and the SHP2 inhibitor PHPS1 in various combinations. Functional changes were assessed by CCK‑8, Transwell, and tube formation assays; protein expression by Western blotting. In vivo validation used a nude mouse xenograft model. Transcriptomics showed IL‑22 markedly upregulated in resistant tissues, with significant correlations between IL22RA1, NFKB1, PTPN11, and STAT3/ROS1/EGFR. GSEA revealed activation of proliferation, metabolic, and EMT pathways. Single‑cell analysis confirmed enrichment of stem‑like (LGR5⁺/OLFM4⁺) subpopulations in resistant cells, with enhanced crosstalk with M2 macrophages and CAFs. Mechanistically, IL‑22 counteracted gefitinib by upregulating p‑SHP2, active p‑Src, p‑AKT, and p‑ERK1/2, promoting proliferation, migration, invasion, and angiogenesis; PHPS1 reversed these effects. In vivo, IL‑22 accelerated tumor growth while PHPS1 suppressed it. Collectively, IL‑22 reduces intracellular ROS via NOX4 downregulation, activating STAT3/SHP2/Src signaling and conferring EGFR‑TKI resistance. These findings highlight the IL‑22/ROS/SHP2 axis as a potential therapeutic target.
Keywords:
Colorectal cancer
EGFR-TKI resistance
Interleukin-22
Reactive oxygen species
SHP2
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