KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer
Open accessAbstract
The biological functions and mechanisms of oncogenic KRAS G12D (KRAS∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS∗ represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS∗-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS∗-IRF2-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC.
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In colon cancer, mutant KRAS inhibits expression of IRF2, which is required for interferon-mediated immune responses.
“In colon cancer, mutant KRAS has been shown to inhibit expression of interferon regulatory factor2 (IRF2), which is required for interferon-mediated immune responses [69].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [69]
SHP099 and G12C-I each decreased the expression of chemokine/cytokine genes that favor immune-suppressive CD11b+ myeloid cells (e.g., CXCL1-5; CCL9).
“while decreasing the expression of those that favor immune-suppressive CD11b+ myeloid cells (e.g., CXCL1-5; CCL9; Chow and Luster, 2014; Kortlever et al., 2017; Liao et al., 2019; Nagarsheth et al., 2017; Fig. 5, I and J).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Liao et al., 2019
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Reck, M., Carbone, D. P., Garassino, M., & Barlesi, F. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.06.001 · Cited by 326 · see citing works
Pyroptosis, metabolism, and tumor immune microenvironment
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Self-citationTumor-associated neutrophils and neutrophil-targeted cancer therapies
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Therapeutic targeting of tumour myeloid cells
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Inflammation-Induced Tumorigenesis and Metastasis
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Mechanisms driving the immunoregulatory function of cancer cells
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Cancer immune evasion, immunoediting and intratumour heterogeneity
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SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
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“tributed to MYC activation or repression of IFN-regulatory factor 2, respectively (Kortlever et al., 2017; Liao et al., 2019).”
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Self-citationInflamed and non-inflamed classes of HCC: a revised immunogenomic classification
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Cancer Stemness Meets Immunity: From Mechanism to Therapy
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Self-citationMechanisms of metastatic colorectal cancer
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“As a result, Kras -mutant CRCs recruit CXCR2-positive myeloid-derived suppressor cells through CXCL3 secretion, impairing immune responses 196 .”
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“Moreover, the expression of CXCL8, a neutrophil chemoattractant, was lower in neutrophils in the EGFR-positive group (online supplemental figure 8A).”
Self-citationEmerging strategies to target RAS signaling in human cancer therapy
Chen, K., Zhang, Y., Qian, L. M., & Wang, P. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01127-w · Cited by 231 · see citing works
“However, oncogenic KRAS promotes tumor cell immune escape and immune therapy resistance through attracting immune-suppressive cells or suppressing cytotoxic cells in a colorectal cancer mouse model [61, 62].”
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Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment
Chen, P., Hsu, W., Chang, A. H., Tan, Z., Lan, Z., Zhou, A. Z., Spring, D. J., Lang, F. F., Wang, Y., & DePinho, R. A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0400 · Cited by 219 · see citing works
“Genes & development 2019;33(11-12):591-609 doi 10.”
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The Multiple Roles of Interferon Regulatory Factor family in Health and Disease
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Resistance mechanisms to immune checkpoint inhibitors: updated insights
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Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer
Bell, H. N., Huber, A. K., Singhal, R., Korimerla, N., Rebernick, R. J., Kumar, R., El-Derany, M. O., Sajjakulnukit, P., Das, N. K., Kerk, S. A., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.013 · Cited by 194 · see citing works
Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC
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NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer
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“IRF2 regulation of GSDMD levels may represent a critical regulatory axis in cancer cell death, given that its loss in cancer leads to immune evasion and resistance to immunotherapy [99].”
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“[64] reported that KRAS-G12D mutation increased the infiltration of bone marrow-derived suppressor cells via the IRF2-CXCL3CXCR2 axis, therapy leading to an immunosuppressive TIME that avoided T cell killing and caused resistance to immunotherapy in colorectal cancer.”
BackgroundSelf-citationBriere, D. M., Li, S., Calinisan, A., Sudhakar, N., Aranda, R., Hargis, L., Peng, D. H., Deng, J., Engstrom, L. D., Hallin, J., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0462 · Cited by 168 · see citing works
“Resistance to anti–PD-1 therapy in KRAS-mutant tumors was overcome through inhibition of downstream KRAS signaling through the IRF2 andMyc pathways (12, 13).”
BackgroundUnderstanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade
Shergold, A. L., Millar, R., & Nibbs, R. J. B. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104258 · Cited by 173 · see citing works
Fueling the Fire: Inflammatory Forms of Cell Death and Implications for Cancer Immunotherapy
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Genomic instability, inflammatory signaling and response to cancer immunotherapy
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Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment
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Drug Resistance in Colorectal Cancer: From Mechanism to Clinic
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Drugging KRAS: Current perspectives and state-of-art review
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“The tumor microenvironment (TME) has been strongly implicated in determining immunotherapeutic outcomes.(4) Cancer-associated lymphatic endothelial cells (LECs) are one of many cell types that promote a suppressive TME and help the tumor escape host immunity.”
BackgroundExploiting the therapeutic implications of KRAS inhibition on tumor immunity
Molina-Arcas, M., & Downward, J. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.02.012 · Cited by 152 · see citing works
Hou, A., Hou, K., Huang, Q., Lei, Y., & Chen, W.-L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00783 · Cited by 147 · see citing works
“The inhibition of CXCR2 overcome anti-PD-1 resistance to KRASG12D-expressing tumors by suppressing KRASG12D-driven MDSCs migration via the CXCL3/CXCR2 axis (145).”
BackgroundHistone demethylase KDM5D upregulation drives sex differences in colon cancer
Li, J., Lan, Z., Liao, W., Horner, J. W., Xu, X., Liu, J., Yoshihama, Y., Jiang, S., Shim, H. S., Slotnik, M., et al. (2023) · Nature · doi:10.1038/s41586-023-06254-7 · Cited by 146 · see citing works
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Hallmarks of Resistance to Immune-Checkpoint Inhibitors
Karasarides, M., Cogdill, A. P., Robbins, P. B., Bowden, M., Burton, E. M., Butterfield, L. H., Cesano, A., Hammer, C., Haymaker, C., Horak, C. E., et al. (2022) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-0586 · Cited by 144 · see citing works
“RAS signaling can upregulate PD-L1 expression on tumor cells by stabilizing PDL1 mRNA (30), an observation that is consistent with the reported association of KRAS expression with increased PD-L1 expression suggesting that the KRAS–IRF3 pathway can support immune suppression and resistance to immunotherapy (31).”
ResultTumor Plasticity and Resistance to Immunotherapy
Horn, L. A., Fousek, K., & Palena, C. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.02.001 · Cited by 142 · see citing works
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“The expansion of immunosuppressive MDSCs is associated with acquired resistance to PD1 blockade 17 .”
Mowat, C., Mosley, S. R., Namdar, A., Schiller, D., & Baker, K. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20210108 · Cited by 134 · see citing works
Neoadjuvant immunotherapy in primary and metastatic colorectal cancer
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Advancements in combining targeted therapy and immunotherapy for colorectal cancer
Singh, M., Morris, V. K., Bandey, I. N., Hong, D. S., & Kopetz, S. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.05.001 · Cited by 138 · see citing works
Self-citationNext batter up! Targeting cancers with KRAS-G12D mutations
Zeissig, M. N., Ashwood, L. M., Kondrashova, O., & Sutherland, K. D. (2023) · Trends in Cancer · doi:10.1016/j.trecan.2023.07.010 · Cited by 128 · see citing works
Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression
Hsu, W.-H., LaBella, K. A., Lin, Y., Xu, P., Lee, R., Hsieh, C.-E., Yang, L., Zhou, A., Blecher, J. M., Wu, C.-J., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1467 · Cited by 125 · see citing works
Self-citationImmunogenic cell death in colon cancer prevention and therapy
Ruan, H., Leibowitz, B. J., Zhang, L., & Yu, J. (2020) · Molecular Carcinogenesis · doi:10.1002/mc.23183 · Cited by 122 · see citing works
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RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms
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Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma
Xuan, W., Hsu, W.-H., Khan, F., Dunterman, M., Pang, L., Wainwright, D. A., Ahmed, A. U., Heimberger, A. B., Lesniak, M. S., & Chen, P. (2022) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-21-0559 · Cited by 117 · see citing works
Self-citationReprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer
Lu, W., Yu, W., He, J., Liu, W., Yang, J., Lin, X., Zhang, Y., Wang, X., Jiang, W., Luo, J., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202012798 · Cited by 112 · see citing works
“…Molecular Medicine 13: e12798 | 2021 1 of 20 2 of 20 EMBO Molecular Medicine 13: e12798 | 2021 ª 2020 The Authors Increasing evidence has indicated that immunosuppressive myeloid cells (IMCs) are a prominent driver of immunotherapy resistance in colorectal cancer (Le et al, 2017; Liao et al, 2019).”
BackgroundZhao, D., Cai, L., Lü, X., Liang, X., Li, J., Chen, P., Ittmann, M., Shang, X., Jiang, S., Li, H., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1352 · Cited by 116 · see citing works
“The poor response of prostate cancer to ICI in the clinic (23) and the key role of MDSCs in suppressing ICI responsiveness in mouse models (28,35,46,47), prompted us to test whether inhibition of the CHD1/IL-6 pathway would improve ICI responsiveness in various mouse models of prostate cancer.”
BackgroundSelf-citationHLA class I loss in colorectal cancer: implications for immune escape and immunotherapy
Anderson, P., Aptsiauri, N., Ruiz-Cabello, F., & Garrido, F. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00634-7 · Cited by 107 · see citing works
Circadian regulation of cancer cell and tumor microenvironment crosstalk
Xuan, W., Khan, F., James, C. D., Heimberger, A. B., Lesniak, M. S., & Chen, P. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.06.008 · Cited by 112 · see citing works
Self-citationRoles and mechanisms of tumour-infiltrating B cells in human cancer: a new force in immunotherapy
Zhang, E., Ding, C., Li, S., Zhou, X., Aikemu, B., Fan, X., Sun, J., Zheng, M., & Yang, X. (2023) · Biomarker Research · doi:10.1186/s40364-023-00460-1 · Cited by 110 · see citing works
“TME-mediated ICI resistance can be induced by cytokines secreted by tumour or stromal cells [6, 7].”
BackgroundThe Immune Microenvironment and Cancer MetastasisPreprint
El-Kenawi, A., Hänggi, K., & Ruffell, B. (2019) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a037424 · Cited by 107 · see citing works
“This includes expression of GM-CSF and CXCL3 in pancreatic cancer and colon carcinoma, respectively (Pylayeva-Gupta et al. 2012; Liao et al. 2019), as well as CCL9 expression in lung cancer in the context of Myc activation (Kortlever et al. 2017).”
BackgroundCancer cell-intrinsic mechanisms driving acquired immune tolerance
Ghorani, E., Swanton, C., & Quezada, S. A. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.004 · Cited by 108 · see citing works
Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
Tang, K. H., Li, S., Khodadadi-Jamayran, A., Jen, J., Han, H., Guidry, K., Chen, T., Hao, Y., Fedele, C., Zebala, J. A., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0369 · Cited by 105 · see citing works
Self-citationOzkan‐Dagliyan, I., Diehl, J. N., George, S. D., Schaefer, A., Papke, B., Klotz‐Noack, K., Waters, A. M., Goodwin, C. M., Gautam, P., Pierobon, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107764 · Cited by 102 · see citing works
“This is consistent with a study of Kras-driven colon cancer, where Kras strongly downregulated IFN-α/γ gene sets, suppressing a T cell immune response (Liao et al., 2019).”
BackgroundResultYan, Y., Zheng, L., Du, Q., Yan, B., & Geller, D. A. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02586-9 · Cited by 104 · see citing works
Convergent inducers and effectors of T cell paralysis in the tumour microenvironment
Hanahan, D., Michielin, O. A., & Pittet, M. J. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00761-z · Cited by 106 · see citing works
Mutant KRAS triggers functional reprogramming of tumor-associated macrophages in colorectal cancer
Liu, H., Liang, Z., Zhou, C., Zeng, Z., Wang, F., Hu, T., He, X., Wu, X., Wu, X., & Lan, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00534-2 · Cited by 100 · see citing works
“In addition to the well-identified cell-intrinsic roles of KRAS, there is a growing recognition that KRAS acts via cell-extrinsic mechanisms to favor tumor progression by engaging with the tumor microenvironment.(9,10) As a major component and key orchestrator of the tumor microenvironment, tumor-associated macrophage…”
BackgroundFalcomatà, C., Bärthel, S., Widholz, S. A., Schneeweis, C., Montero, J. J., Toska, A., Mir, J., Kaltenbacher, T., Heetmeyer, J., Swietlik, J. J., et al. (2022) · Nature Cancer · doi:10.1038/s43018-021-00326-1 · Cited by 99 · see citing works
The immune microenvironment of colorectal cancer
Kennel, K. B., & Greten, F. R. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00872-1 · Cited by 100 · see citing works
Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance
Reita, D., Pabst, L., Pencreach, E., Guérin, É., Dano, L., Rimelen, V., Voegeli, A., Vallat, L. D., Mascaux, C., & Beau‐Faller, M. (2022) · Cancers · doi:10.3390/cancers14051321 · Cited by 101 · see citing works
“Prognostic value of KRAS mutations are controversial [32,33].”
BackgroundZhou, C., Li, W., Zhenxing, L., Wu, X., Cheng, S., Peng, J., Zeng, K., Li, W., Lan, P., Yang, X., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44779-1 · Cited by 100 · see citing works
“A study by DePinho et al. reinforced this therapeutic strategy by showing that inhibition of myeloid-derived suppressor cell recruitment could overcome resistance of tumors expressing KRAS G12D to anti-PD1 therapy 49 .”
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Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy
Hao, Z., Li, R., Wang, Y., Li, S., Hong, Z., & Han, Z. (2021) · Biomarker Research · doi:10.1186/s40364-021-00333-5 · Cited by 94 · see citing works
“IRF2 inhibition was found in KRAS-mutated colorectal cancer, contributing to the augmented expression of CXCL3, which binds to CXCR2 on MDSCs to induce migration [25].”
BackgroundSelf-citationUnveiling the role of KRAS in tumor immune microenvironment
Xu, M., Zhao, X., Wen, T., & Qu, X. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.116058 · Cited by 93 · see citing works
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“reported that oncogenic KRAS represses immune response through the KRAS/interferon regulatory factor 2 axis, resulting in low expression of C- XC motif chemokine ligand 3 and acquired resistance to immunotherapy in colorectal cancer.(47) Additionally, our results directly demonstrate a suppressive immune microenvironm…”
BackgroundTwo-Faced Roles of Tumor-Associated Neutrophils in Cancer Development and Progression
Mukaida, N., Sasaki, S., & Baba, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103457 · Cited by 91 · see citing works
Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer
Choi, Y. W., Kim, Y. H., Oh, S. Y., Suh, K. W., Kim, Y., Lee, G., Yoon, J. E., Park, S. S., Lee, Y., Park, Y. J., et al. (2021) · Advanced Science · doi:10.1002/advs.202002497 · Cited by 87 · see citing works
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Self-citationThe roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy
Ma, Q., Zhang, W., Wu, K., & Shi, L. (2025) · Molecular Cancer · doi:10.1186/s12943-024-02218-1 · Cited by 88 · see citing works
“Restoring IRF2 expression or inhibiting CXCR2, a CXCL3 receptor, reduces MDSC infiltration and enhances T cell-mediated anti-tumor responses in colorectal cancer [133].”
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BackgroundInfluential
- Authors
- Liao, W., Overman, M. J., Boutin, A. T., Shang, X., Zhao, D., Dey, P., Li, J., Wang, G., Lan, Z., Li, J., Tang, M., Jiang, S., Ma, X., Chen, P., Katkhuda, R., Korphaisarn, K., Chakravarti, D., Chang, A., Spring, D. J., Chang, Q., Zhang, J., Maru, D. M., Maeda, D. Y., Zebala, J. A., Kopetz, S., Wang, Y. A., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Syntrix Biosystems (United States) (US)
- Corresponding author
- Wang, Y. Alan
- DePinho, Ronald A.
- ORCID
- Liao, Wenting
- Overman, Michael J.
- Shang, Xiaoying
- Zhao, Di
- Dey, Prasenjit
- Li, Jiexi
- Wang, Guocan
- Li, Jun
- Tang, Ming
- Jiang, Shan
- Ma, Xingdi
- Chen, Peiwen
- Korphaisarn, Krittiya
- Chakravarti, Deepavali
- Chang, Andrew
- Spring, Denise J.
- Chang, Qing
- Zhang, Jianhua
- Maru, Dipen M.
- Maeda, Dean Y.
- Zebala, John A.
- Kopetz, Scott
- Wang, Y. Alan
- DePinho, Ronald A.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 35
- Issue
- 4
- Pages
- 559-572.e7
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC6467776
- OpenAlex
- W2923548794
- Cited by
- 617
- References
- 63
- Citations by year
- 2026: 68 · 2025: 91 · 2024: 104 · 2023: 89 · 2022: 97 · 2021: 86 · 2020: 62 · 2019: 20
- FWCI
- 27.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 CA084628, PO1 CA117969)
- MD Anderson Colorectal Cancer Moon Shot funds
- National Basic Research Program of China (2015CB554002)
- National Natural Science Foundation of China (81672886, 81773101, 81872401)
- CPRIT (RP170067)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- KRAS G12D, IRF2, CXCL3, CXCR2, colorectal cancer, immune checkpoint inhibitor resistance, anti-PD-1 therapy, myeloid-derived suppressor cells, tumor microenvironment, immunosuppression, transcriptional repression, patient selection
- MeSH terms
- Myeloid-Derived Suppressor Cells, Antineoplastic Agents, Immunological, Adult, Aged, Animals, Cell Movement, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Colorectal Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Tumor Escape, Chemokines, CXC, Receptors, Interleukin-8B, Adenomatous Polyposis Coli Protein, Cell Line, Tumor, Interferon Regulatory Factor-2, Young Adult, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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