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Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response. This immunophenotype is not exclusive to dMMR CRCs but comprises a subset of MMR proficient (pMMR) CRCs. Single-cell spatial analysis and in vitro cell co-cultures indicate that interferon-producing cytotoxic T cells induce overexpression of antigen presentation in adjacent macrophages and tumor cells, including MHC class II invariant chain CD74. dMMR CRCs expressing high levels of CD74 respond to ICI and a subset of CD74 high pMMR CRC patients show better progression free survival when treated with ICI. Therefore, CD74 abundance can identify the constitutive interferon-high immunophenotype determining clinical benefit in CRC, independently of tumor mutational burden or MMR status., Competing Interests: Declaration of interests A.A.S., P.A., K.C., and F.C. hold a pending patent (patent no 2401121.5). C.A. is on the advisory board of or has a consultant role with Takeda; and is invited speaker with compensation for Merck. F.B. is on the advisory board of Servier, AAA Novartis and is invited speaker with compensation from Eli-Lilly, MSD, EISAI, Bristol Myers Squibb, AstraZeneca, and Pierre Fabre. R.I. is on the advisory board of or has a consultant role with Bayer. E.C.S. is on the advisory board of, has a consultant role with or has received travel support from: Amal Therapeutics, Aptitude Health, Amgen, Astellas, Astra Zeneca, Beigene, BMS, Celgene, Daiichi Sankyo, Elsevier, Everest Clinical Research, First Word Group, Five Prime Therapeutics, Gritstone Oncology, Imedex, Merck, MSD, My Personal Therapeutics, Novartis, Pfizer, Roche, Sai-Med, Servier, Viracta, and Zymeworks; holds research funding (to Institution) from BMS and Astra Zeneca; and holds leadership roles in: EORTC GI Clinical Trials Group, ESMO Guidelines Committee and ESMO GI Faculty. S.L. is on the advisory board of or has a consultant role with: Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm, Beigene, Fosum, Nimbus Therapeutics; holds research funding (to Institution) from: Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; and has received personal honoraria as invited speaker from Amgen, Astra Zeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier. C.C. is on the advisory board of or has a consultant role with: Astra Zeneca, Bicara Therapeutics, BMS, Lilly, Merck, Mirati, MSD, Nordic Pharma, Roche, Pierre Fabre, Rottapharm, Takeda, and Tempus; is an invited speaker with compensation for Amgen, Bayer, Merck Serono, MSD, Pierre Fabre, Servier, and Takeda; and holds research grants by Amgen, Merck, Pierre Fabre, Roche, Seagen (Pfizer), Servier, and Tempus. M.R.-J. has attended advisory boards, chaired educational meetings, consulted for, or been reimbursed travel, accommodation and registration at national/international meetings by Bristol Myers Squibb/BMS, Merk Sharp & Dohme/MSD, Roche Diagnostics, Servier, Jazzpharma, Astellas and Agilent; and holds a research grant from Pfizer. E.F. holds an advisory or consulting role with Astellas Pharma, Pfizer, Bicycle Therapeutics, and BMS; holds research funding (to Institution) from Repair Therapeutics, Bicycle Therapeutics, Artios Pharma, Seagen, Amgen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Tahio Pharmaceutical, Pfizer, Roche, Daiichi Sankyo, Gilead Sciences, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, HUTCHMED, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma, Acerta Pharma, ADC Therapeutics, Arcus Biosciences, Astella Pharma, Astra Zeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Calithera Biosciences, Carrick Therapeutics, CASI Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, Deciphera, Lilly, Ellipses Pharma, Exelixis, Fore Biotherapeutics, GI Therapeutics, Genentech, H3 Biomedicine, Ignyta/Genentech/Roche, Immunocore, Immunomedics, Incyte, Instil Bio, Iovance Biotherapeutics, Janssen, Kronos Bio, Lupin Pharmaceuticals, Macrogenics, Menarini, Merck KGaA, Millenium Pharmaceuticals, Nerviano Medical Sciences, Oxford VacMedix, Plexxicon, QED Therapeutics, Ribon Therapeutics, SERVIER, Stemline Therapeutics, Synthon, Tesaro, PMV Pharma and Takeda; has had travel, accommodation or expenses reimbursed by: Repair Therapeutics, CARIS life Science, Seagen, Sapience Pharma, Bicycle Therapeutics, and Erasca Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)