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Most patients show limited response to standard\u2010of\u2010care chemotherapy with or without radiotherapy, and only a minority of cases are amenable to targeted therapies like poly\u2010ADP ribose polymerase (PARP) inhibitors and HER2\u2010directed therapies. Recent immunotherapy clinical trials have demonstrated remarkable efficacy, not only in mismatch repair deficient (MMRd) tumors but also in a subset of mismatch repair\u2010proficient (MMRp) tumors. However, the immune microenvironment and its relationship to other therapeutic targets in MMRp endometrial carcinoma remains poorly understood. Here, we characterize the immune microenvironment of p53abn endometrial carcinoma, the most clinically aggressive subtype of MMRp endometrial carcinoma, and correlate antitumor immune signatures with other targetable alterations. We accrued 256 treatment\u2010na\u00efve p53abn endometrial carcinomas and systemically profiled T\u2010cell, B\u2010cell, myeloid, and tumor\u2010cell populations with multiplex immunofluorescence to assess the tissue localization and functional status of immune cells. Shallow whole\u2010genome sequencing was performed on a subset of 126 cases. Patterns of immune infiltration were compared to survival outcomes and mutational signatures. Mixture modeling divided p53abn endometrial carcinoma into tumor\u2010infiltrating lymphocyte (TIL)\u2010rich and TIL\u2010poor subsets. Over 50% of tumors were TIL\u2010rich. TIL\u2010rich cases overexpressed targetable immune evasion molecules and were associated with longer overall and disease\u2010specific survival in multivariate analysis. This effect was particularly pronounced in advanced stage disease and in patients who did not receive adjuvant chemotherapy. TIL did not associate with homologous recombination deficient mutational signatures or HER2 amplification. Our findings demonstrate a biological rationale for immunotherapy in a substantial subset of patients with p53abn endometrial cancer and may help inform combination therapies with immune checkpoint inhibition, PARP inhibitors, and anti\u2010HER2 agents. \u00a9 2025 The Author(s). <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6429","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T06:38:06Z","timestamp":1744612686000},"page":"292-305","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Activated immune infiltrates expand opportunities for targeted therapy in <scp><i>p53<\/i><\/scp>\u2010abnormal endometrial carcinoma"],"prefix":"10.1002","volume":"266","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7002-1083","authenticated-orcid":false,"given":"Spencer D","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Faculty of Medicine The University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby","family":"Thornton","sequence":"additional","affiliation":[{"name":"Molecular and Advanced Pathology Core (MAPcore) The University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Chow","sequence":"additional","affiliation":[{"name":"Molecular and Advanced Pathology Core (MAPcore) The University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Milne","sequence":"additional","affiliation":[{"name":"Trev and Joyce Deeley Research Centre 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