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However, ensuring the availability of all modalities in routine clinical practice remains challenging. Comprehensive molecular profiling is often constrained by cost and turnaround time, leaving histopathology as the most consistently available modality across institutions. In addition, variability in staining protocols, scanning devices, patient demographics, and outcome distributions across centers undermines the generalizability of models trained under controlled conditions with complete inputs. To address these challenges, we developed the Domain\u2010Adaptive Incomplete Multimodal Stratification framework (DAIMS). DAIMS leverages paired histopathology, genomic, and clinical data during training to learn generalizable disease representations and uses histology\u2010derived surrogate latent representations when auxiliary modalities are unavailable, enabling flexible histology\u2010only inference. Trained on TCGA samples and validated on two independent European and East Asian cohorts comprising 842 patients, DAIMS consistently outperformed state\u2010of\u2010the\u2010art methods. Adapted DAIMS improved the C\u2010index by 5.6%\u201313.9% on F1CRC and 4.1%\u20139.0% on SURGEN compared with baseline methods. DAIMS improved within\u2010cohort prognostic discrimination and localized prognostically relevant morphological patterns that remained stable across institutions. Our evaluation showed that DAIMS achieved generalizable survival stratification across disease stages, molecular subgroups, and treatment\u2010defined patient\u00a0groups.<\/jats:p>","DOI":"10.1002\/advs.78019","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:03:53Z","timestamp":1790744633000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Generalizable Multimodal Model for Treatment\u2010Stratified Risk and Survival Assessment under Real\u2010World Constraints: A Multi\u2010Center Study of Colorectal Cancer"],"prefix":"10.1002","author":[{"given":"Chuangjie","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Pathology, the First Affiliated Hospital University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4050-101X","authenticated-orcid":false,"given":"Zheyi","family":"Ji","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center UChicago Medicine Chicago USA"},{"name":"Department of Human Genetics The University of Chicago Chicago USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8948-1352","authenticated-orcid":false,"given":"Chang","family":"He","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center UChicago Medicine Chicago USA"},{"name":"Department of Human Genetics The University of Chicago Chicago USA"},{"name":"Committee on Genetics, Genomics and Systems Biology The University of Chicago Chicago USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiying","family":"Wang","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center UChicago Medicine Chicago USA"},{"name":"Department of Human Genetics The University of Chicago Chicago USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Luo","sequence":"additional","affiliation":[{"name":"Changsha Taifang Yaoyu Technology Co., Ltd. Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohu","family":"Jing","sequence":"additional","affiliation":[{"name":"Changsha Chuangke Software Co., Ltd. Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4216-3876","authenticated-orcid":false,"given":"Fang","family":"Yan","sequence":"additional","affiliation":[{"name":"Shanghai AI Laboratory Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8325-3596","authenticated-orcid":false,"given":"Yirong","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai AI Laboratory Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3754-2458","authenticated-orcid":false,"given":"Linhao","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics Harvard Medical School Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-4122","authenticated-orcid":false,"given":"Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"Ant Healthcare (AFU), Ant Group Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Le Lu","sequence":"additional","affiliation":[{"name":"Ant Healthcare (AFU), Ant Group Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6184-3931","authenticated-orcid":false,"given":"Yuming","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Wake Forest University School of Medicine Winston\u2010Salem USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3597-9090","authenticated-orcid":false,"given":"Xiyue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics Harvard Medical School Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7376-2677","authenticated-orcid":false,"given":"Chengyun","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases The First Affiliated Hospital University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0316-8365","authenticated-orcid":false,"given":"Junhan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Comprehensive Cancer Center UChicago Medicine Chicago USA"},{"name":"Department of Biomedical Informatics Harvard Medical School Boston USA"},{"name":"Department of Pediatrics The University of Chicago Chicago USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"3","key":"e_1_2_13_2_1","first-page":"145","article-title":"Colorectal Cancer Statistics, 2020","volume":"70","author":"Siegel R. 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