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This study investigated the tumor microenvironment (TME) in relation to EGFRI eligibility\u2015clinically defined by factors such as tumor sidedness (e.g., left\u2010sided), RAS\/BRAF wild\u2010type status, and microsatellite stability (MSS)\u2015using integrated single\u2010cell RNA sequencing (scRNA\u2010seq), with bulk RNA\u2010seq and spatial transcriptomics validation. We found cancer cell features reflected EGFRI eligibility more strongly than sidedness. EGFRI eligible tumors exhibited high Epiregulin (EREG) expression by cancer cells. Cell interaction analysis revealed a specific \u201cEREG\/EGFR\/CSF axis\u201d in EGFRI eligible CRC: EREG derived from cancer cell stimulates EGFR\u2010expressing non\u2010myCAF subtypes of cancer\u2010associated fibroblasts (CAFs), which signal via CSF to M1\/M2\u2010like Tumor\u2010Associated Macrophages\/Monocytes (TAM\/TAMo), potentially promoting M2 polarization. Spatial analysis confirmed the proximity of these interacting cell populations and localized EGFR pathway activation near cancer cells specifically in eligible tumors. This study provides a TME\u2010centric view of EGFRI eligibility, identifying a key intercellular communication network driving differential responses. These findings suggest TME features could offer more precise patient stratification than sidedness alone, potentially improving CRC therapeutic strategies.<\/jats:p>","DOI":"10.1002\/cam4.71853","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T14:58:07Z","timestamp":1777301887000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multi\u2010Transcriptomic Analysis Reveals That\n                    <scp>EREG<\/scp>\n                    \u2010Driven\n                    <scp>TME<\/scp>\n                    Crosstalk Defines Anti\u2010\n                    <scp>EGFR<\/scp>\n                    Response in Colorectal Cancer"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2908-9056","authenticated-orcid":false,"given":"Atsuki","family":"Taniguchi","sequence":"first","affiliation":[{"name":"Department of Gastroenterological Surgery, Graduate School 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