Abstract
Several epidemiological and preclinical studies suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) exert anticancer activity at multiple stages of colorectal cancer (CRC) progression. However, inconsistent clinical evidence and the lack of a clearly defined molecular mechanism underlying the antitumor effects of n-3 PUFAs have raised doubts about their efficacy as anticancer therapies. To address these issues, we investigated the effects of the n-3 PUFA docosahexaenoic acid (DHA) in a collection of CRC patient-derived tumor organoids (PDTOs), a powerful platform for functional analysis of patient-specific tumors. DHA treatment markedly reduced CRC cell viability in a time- and concentration-dependent manner without inducing apoptosis. CRC-derived PDTOs exhibited pronounced sensitivity to DHA, irrespective of KRAS or TP53 mutational status, whereas organoids from normal colon tissue were less affected. Mechanistically, DHA induced ferroptosis in both CRC cells and PDTOs, as evidenced by lipid peroxide accumulation and partial rescue by ferroptosis inhibitors. Fluorescently labeled DHA localized predominantly to the endoplasmic reticulum and mitochondria, where it promoted oxidative stress. Moreover, DHA impaired the regrowth of oxaliplatin-tolerant persister cells and enhanced oxaliplatin efficacy in sequential treatment models. Together, these findings indicate that exploiting the intrinsic oxidative vulnerability of cancer cells with DHA may represent a promising, low-toxicity strategy to enhance chemotherapy efficacy and target drug-tolerant persister cells in colorectal cancer.
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Requests for further information and resources should be directed to and will be fulfilled by the lead contact Luca Primo (luca.primo@unito.it).
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Acknowledgements
This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) grant IG-23211 to LP and MFAG-25040 to AP; FPRC 5 × 1000 Ministero della Salute 2022 CARESS to AP; MUR (Dipartimenti di Eccellenza DM 11/05/2017 n262) to the Department of Oncology, University of Turin (2023–2027 14586 DIORAMA); MUR PRIN2022A93K7S_003 to LP and PRIN2022ECBA39 to VM; Italian Ministry of Health, Ricerca Corrente 2025. VCL was supported by MSCA program fellowship and by Fondazione Veronesi fellowship. We are grateful to Jessica Enriquez for her assistance with microscopic imaging and to Donatella Valdembri for providing antibodies and for her valuable suggestions in the immunofluorescence analysis.
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MVM, VM, LdB, and LP conceived the study; LdB, MVM, EM, VCL, and VM performed cells and organoids experiments; BP, LdB and VM performed immunofluorescence, confocal microscopy and FACS experiments; AP, BP, LdB, and VM performed imaging analysis; AB, LT, and AP gave conceptual advice; LP, LdB, and VM supervised the project and interpreted the results. LP drafted the initial manuscript; MVM, LdB, VM, AP, AB and LT revised and edited the final version. LP, AP, and VM acquired funding. All authors reviewed and approved the final manuscript.
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LT has received research grants from Menarini, Merck KGaA, Merus, Pfizer, Servier and Symphogen outside the submitted work. The other authors declare no competing interests.
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All methods were performed in accordance with the relevant guidelines and regulations. Human PDTOs and intestinal organoids were derived from CRC liver metastases and from healthy intestine. These studies were approved respectively, by medical ethical committees of Fondazione del Piemonte per l’Oncologia FPO - IRCCS (PROFILING protocol No. 001-IRCC-00IIS-10, version 11.0, updated July 13, 2022) and by ethical committee of each participating center to the ALFAOMEGA Master Observational Trial (NCT04120935). All patients provided written informed consent.
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di Blasio, L., Vara-Messler, M., Peracino, B. et al. Omega-3 fatty acid DHA induces ferroptosis in colorectal cancer patient-derived organoids and drug-tolerant cells. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08744-8
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DOI: https://doi.org/10.1038/s41419-026-08744-8
