{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:31:20Z","timestamp":1782487880430,"version":"3.54.5"},"reference-count":270,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide, with molecular heterogeneity complicating early detection and treatment stratification. The insulin-like growth factor (IGF) axis interacts bidirectionally with immune regulatory mechanisms in ways that shape tumor phenotype and therapeutic vulnerability. This review synthesizes evidence on how IGF signaling orchestrates immunosuppression through effects on tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, while inflammatory cytokines reciprocally modulate IGF bioavailability. Three mechanistic principles emerge: IGF binding protein 2 (IGFBP-2) functions as a central coordinator linking growth factor signaling to immune evasion through STAT3-dependent pathways driving M2 macrophage polarization and regulatory T cell differentiation; IGF\u2013immune crosstalk varies considerably across molecular subtypes, with microsatellite-stable tumors exhibiting high reliance on IGF-I receptor-mediated immune silencing; and local paracrine IGF production increasingly dominates over systemic regulation as disease progresses. These bidirectional connections establish self-reinforcing circuits that determine whether tumors remain immunologically responsive or develop immune exclusion. Multi-marker panels incorporating IGFBP-2 alongside complementary biomarkers have shown improved diagnostic performances for early CRC detection, underscoring the need for the large-scale prospective clinical evaluation of IGF network components as biomarkers for CRC in diverse populations. The convergence of IGF signaling with checkpoint regulation suggests that combined targeting warrants investigation for resistance in tumors lacking effective immunotherapy options.<\/jats:p>","DOI":"10.3390\/ijms27083666","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T13:22:47Z","timestamp":1776691367000},"page":"3666","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bidirectional Interactions Between Immune Regulation and the Insulin-like Growth Factor Axis in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2271-4560","authenticated-orcid":false,"given":"Hilmaris","family":"Centeno-Girona","sequence":"first","affiliation":[{"name":"Division of Shared Resources and Scientific Operations, University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2778-4696","authenticated-orcid":false,"given":"Sheila N.","family":"L\u00f3pez-Acevedo","sequence":"additional","affiliation":[{"name":"Division of Shared Resources and Scientific Operations, University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2612-9673","authenticated-orcid":false,"given":"Camille","family":"Zen\u00f3n-Mel\u00e9ndez","sequence":"additional","affiliation":[{"name":"Division of Shared Resources and Scientific Operations, University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga L.","family":"D\u00edaz-Miranda","sequence":"additional","affiliation":[{"name":"Division of Shared Resources and Scientific Operations, University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9921-4276","authenticated-orcid":false,"given":"Elba V.","family":"Caraballo","sequence":"additional","affiliation":[{"name":"Division of Shared Resources and Scientific Operations, University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico"},{"name":"Division of Clinical and Translational Cancer Research, University of Puerto Rico Comprehensive Cancer Center, San Juan 00936, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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