{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T05:04:35Z","timestamp":1784091875594,"version":"3.55.0"},"reference-count":76,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"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) exhibits a highly heterogeneous tumor immune microenvironment (TME), ranging from \u201cimmune-inflamed\u201d to \u201cimmune-desert\u201d or \u201cimmune-excluded\u201d phenotypes. Understanding how immune cell composition, cytolytic activity (CYT) and genomic alternations shape tumor-immune interactions is critical for improving immunotherapy outcomes. We analyzed TCGA-COAD and TCGA-READ datasets to evaluate immune competency, CYT, immune subtypes, microsatellite instability (MSI), and genomic instability, including somatic mutations, copy number aberrations (CNAs), and chromothriptic events. Immune cell infiltration was correlated with CYT levels, immune checkpoint expression, and immune-related gene signatures. Immune-competent (IC) tumors were predominantly CYT-high, enriched in stromal and immune scores, and exhibited distinct TME characteristics compared with immune-deficient (ID) tumors. IC\/CYT-high tumors expressed higher levels of immune checkpoints (PD-1, PD-L1, CTLA-4, IDO1\/2, LAG-3) and cytokines\/chemokines (C1QA\/B\/C, CXCL9\/10\/11, CXCL13). Differences in immune infiltration were observed across tumors with significant mutations and copy number alterations. No prognostic difference was observed between CYT-high and CYT-low patients, indicating that CYT reflects immune activation rather than clinical outcome. Functionally, stimulated CD8+ T cells exhibited cytotoxicity activity against MSI-high (HCT-116) and microsatellite-stable (HT-29) CRC cells, with MSI-H cells showing higher sensitivity. Dynamic 3D co-culture demonstrated tumor-guided T cell infiltration and retention of CD8 expression, and co-culture was associated with moderate upregulation of cytotoxicity-related genes GZMA and PRF1 within the system. Cytotoxic activity decreased at lower effector-to-target ratios, highlighting the importance of effector dose. Overall, these findings link CYT, immune competency, MSI status, and genomic instability to T cell cytotoxic responses, providing insights into tumor-immune interactions, and suggest potential associations relevant for immunotherapy research in CRC.<\/jats:p>","DOI":"10.3390\/ijms27146180","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:16:28Z","timestamp":1783689388000},"page":"6180","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune Cytolytic Activity Correlates with Tumor Microenvironmental Aberrations in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4267-6849","authenticated-orcid":false,"given":"Stephanie","family":"Agioti","sequence":"first","affiliation":[{"name":"Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, 1516 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Georgoulias","sequence":"additional","affiliation":[{"name":"Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, 1516 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3641-1488","authenticated-orcid":false,"given":"Ilias","family":"Georgakopoulos-Soares","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Toxicology, College of Pharmacy, Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1659-4993","authenticated-orcid":false,"given":"Maria-Ioanna","family":"Christodoulou","sequence":"additional","affiliation":[{"name":"Tumor Immunology and Biomarkers Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, 1516 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4625-5562","authenticated-orcid":false,"given":"Apostolos","family":"Zaravinos","sequence":"additional","affiliation":[{"name":"Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, 1516 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"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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