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In this study, we combine intermittent low\u2010dose ERL\u2009\u00b1\u2009SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor\u2010associated immune modulation. At clinically relevant doses, short\u2010term (16\u2009weeks) and long\u2010term (46\u2009weeks) ERL\u2009\u00b1\u2009SUL administration results in near\u2010complete tumor suppression in Pirc colon and duodenum (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). We identify a low\u2010dose threshold for significant antitumor activity in Pirc rats given SUL at 125\u2009ppm in the diet plus ERL at 5\u2009mg\/kg body weight via twice\u2010weekly oral gavage (SUL125\u2009+\u2009ERL5\u2009\u00d7\u20092). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL\u2009\u00b1\u2009SUL upregulates the corresponding MHC and immune\u2010associated factors in a subset of Pirc colon polyps<jats:italic>,<\/jats:italic> Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient\u2010derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125\u2009+\u2009ERL5\u2009\u00d7\u20092 increases tumor\u2010associated Cd4<jats:sup>+<\/jats:sup> T cells by ~2.6\u2010fold (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), with no apparent effect on Cd8<jats:sup>+<\/jats:sup> T cells. The treatment also increases tumor\u2010associated Cd68<jats:sup>+<\/jats:sup> cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and decreases Foxp3<jats:sup>+<\/jats:sup> (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and Arg1<jats:sup>+<\/jats:sup> (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) cells. Thus, intermittent low\u2010dose ERL\u2009+\u2009SUL treatment enhances tumor\u2010associated MHC expression and remodels the immune cell niche toward a more permissive \u201chelper\u201d immune microenvironment. We conclude that early immune\u2010interception strategies targeting interferon\u2010\u03b3 signaling may benefit FAP patients at drug doses below the clinical standard of care.<\/jats:p>","DOI":"10.1002\/ijc.35409","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T12:58:31Z","timestamp":1741784311000},"page":"355-370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antitumor efficacy of intermittent low\u2010dose erlotinib plus sulindac via <scp>MHC<\/scp> upregulation and remodeling of the immune cell niche"],"prefix":"10.1002","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0370-5829","authenticated-orcid":false,"given":"Chakrapani","family":"Tripathi","sequence":"first","affiliation":[{"name":"Center for Epigenetics &amp; Disease Prevention, Texas A&amp;M HEALTH, and Department of Translational Medical Sciences Texas A&amp;M University Naresh K. 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Vashisht College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Altaf","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Chemopreventive Agent Development Research Group, Division of Cancer Prevention National Cancer Institute  Rockville Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shizuko","family":"Sei","sequence":"additional","affiliation":[{"name":"Chemopreventive Agent Development Research Group, Division of Cancer Prevention National Cancer Institute  Rockville Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacklyn","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Clinical Cancer Prevention The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahira","family":"Zaheer","sequence":"additional","affiliation":[{"name":"Department of Clinical Cancer Prevention The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krishna M.","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Clinical Cancer Prevention The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Powel H.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Clinical Cancer Prevention The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle I.","family":"Savage","sequence":"additional","affiliation":[{"name":"Department of Clinical Cancer Prevention The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Vilar","sequence":"additional","affiliation":[{"name":"Department of Clinical Cancer Prevention The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6221-7366","authenticated-orcid":false,"given":"Praveen","family":"Rajendran","sequence":"additional","affiliation":[{"name":"Center for Epigenetics &amp; Disease Prevention, Texas A&amp;M HEALTH, and Department of Translational Medical Sciences Texas A&amp;M University Naresh K. 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