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Published on: June 27, 2025
Targeting interleukin-17 enhances tumor response to immune checkpoint inhibitors in colorectal cancer
Shun Li1, Ruisi Na1, Xuehan Li1
1Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin 150081, PR China; Department of Phase 1 Trials Center, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Nangang District, Harbin 150081, PR China; Heilongjiang Province Key Laboratory of Molecular Oncology, No. 150 Haping Road, Nangang District, Harbin, Heilongjiang Province 150081, PR China.
Although immune checkpoint inhibitors (ICIs) have gained much attention in managing cancer, only a minority of patients, especially those with tumors that have been classified as immunologically "cold" such as microsatellite stable (MSS) colorectal cancers (CRC), experience clinical benefit from ICIs. Surprisingly, interleukin-17 (IL-17) and its primary source Th17 are enriched in CRC and inversely associated with patient outcome. Our previous study revealed that IL-17A could upregulate programmed death-ligand 1 (PD-L1) expression and impede the efficacy of immunotherapy. IL-17, therefore, can be a possible target to sensitize tumor cells to ICIs. The detailed clinical results from our trial, which is the first to show the benefits of the combination of anti-PD-1 with anti-IL-17 therapy for MSS CRC, have also been presented. In this review, we highlight the role of IL-17 in ICIs resistance and summarize the current clinical evidence for the use of combination therapy. Directions for future strategies to warm up immunologically "cold" MSS CRCs have also been proposed.
Although immune checkpoint inhibitors (ICIs) have gained much attention in managing cancer, only a minority of patients, especially those with tumors that have been classified as immunologically "cold" such as microsatellite stable (MSS) colorectal cancers (CRC), experience clinical benefit from ICIs. Surprisingly, interleukin-17 (IL-17) and its primary source Th17 are enriched in CRC and inversely associated with patient outcome. Our previous study revealed that IL-17A could upregulate programmed death-ligand 1 (PD-L1) expression and impede the efficacy of immunotherapy. IL-17, therefore, can be a possible target to sensitize tumor cells to ICIs. The detailed clinical results from our trial, which is the first to show the benefits of the combination of anti-PD-1 with anti-IL-17 therapy for MSS CRC, have also been presented. In this review, we highlight the role of IL-17 in ICIs resistance and summarize the current clinical evidence for the use of combination therapy. Directions for future strategies to warm up immunologically "cold" MSS CRCs have also been proposed.
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