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Standardized density-based metrics such as the Immunoscore have demonstrated prognostic value but cannot capture the spatial interactions among cells that underlie immune\u2013tumor biology. We introduce a deep learning framework that integrates two complementary axes of analysis: Cu-Cyto, a deep learning\u2013based image cytometry platform that detects and classifies approximately twenty cell types from standard immunohistochemistry-stained whole-slide images, using a bit-pattern kernel-filtering algorithm to prevent multi-counting and an off-target labeling strategy for precise nuclear-center localization; and the Co-Localization Index, which converts the classification probabilities and coordinates produced by Cu-Cyto into a single quantitative measure of co-localization between two or three cell types. We illustrate this framework through CD103\u207aCD8\u207a tissue-resident memory\u2013like T cells in rectal cancer treated with neoadjuvant chemoradiotherapy: their stromal but not intratumoral density independently predicts relapse-free survival. This divergence, which compartment-aware density alone cannot explain, motivates a metric that captures within-compartment spatial relationships. The Co-Localization Index extends naturally to three-cell interactions, providing a quantitative readout of the tri-cellular biology among CD103\u207aCD8\u207a T cells, tumor cells, and stromal components. Prospective validation in independent rectal-cancer cohorts, addressing watch-and-wait organ preservation and adjuvant chemotherapy decisions, will determine whether this spatial-cellular framework translates into routine clinical decision support with potential extension to other solid tumor contexts.<\/jats:p>","DOI":"10.1007\/s10147-026-03182-0","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:46:22Z","timestamp":1788867982000},"page":"2556-2565","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From cell counts to cellular interactions: Cu-Cyto and the co-localization index as a spatial framework for the tumor immune microenvironment of rectal cancer"],"prefix":"10.1007","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4208-7138","authenticated-orcid":false,"given":"Kimihiro","family":"Yamashita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Nagasaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukari","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Tachibana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Kagiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Imai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Tsuneki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Ando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuna","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumiko","family":"Miyashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunori","family":"Otowa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Urakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironobu","family":"Goto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Kanaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsugu","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryohei","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Fukumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kakeji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"3182_CR1","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/nrclinonc.2017.101","volume":"14","author":"WH Fridman","year":"2017","unstructured":"Fridman WH, Zitvogel L, Saut\u00e8s-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. 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T.F. received grants or contracts from Alfresa Pharma Corporation and Otsuka Pharmaceutical Factory, Inc., royalties or licenses from Alfresa Pharma Corporation, and holds a patent registered with Alfresa Pharma Corporation. All other authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable. This review article does not contain any new studies with human participants or animals performed by the authors. All clinical data referenced in this review have been previously reported and approved by the respective institutional review boards.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}]}}