Tumor-infiltrating immature innate lymphoid cells in colorectal cancer are biased toward ILC1/tissue-resident NK cell differentiation.
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Marchalot A, Ljunggren M, Stamper C, Weigel W, Tibbitt CA, Meininger I, Pandey RV, Franklin M, Bassett JW, Wirth L, Colorectal Study Group , Lindforss U, Jansson-Palmer G, Nordenvall C, Mjösberg J
Nat Commun 17 (1) - [2026-03-27; online 2026-03-27]
Peritoneal metastases (PM) occur in 10% of patients with colorectal cancer (CRC) and are linked to poor outcomes. Although dysregulated innate lymphoid cells (ILC) have been described in CRC, their function in CRC-PM remains unclear. Here, we analyze tumor samples from CRC and CRC-PM patients using single-cell RNA sequencing (11 patients), flow cytometry (8 patients) and differentiation assays (24 patients). Healthy colon, primary CRC and CRC-PM tumors are infiltrated by heterogeneous populations of ILC3, ILC2, ILC1, tissue resident (tr)NK cells and conventional (c)NK cells. Compared to healthy colons, primary CRC and CRC-PM tumors are depleted of ILC3 but enriched for ILC1, trNK cells and cNK cells. CRC and CRC-PM tumors harbor two immature ILC populations, early NK and naïve (n)ILC, with nILCs being transcriptionally skewed toward ILC1 and trNK cells. Indeed, co-culture of isolated nILCs with OP9-DL1 cells induces intratumoral nILC differentiation into ILC1/trNK-like cells. These findings help understand the immune pathogenesis of CRC and CRC-PM and provide insights for future ILC1 and NK cell-based therapies.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 41896575
DOI 10.1038/s41467-026-71085-9
Crossref 10.1038/s41467-026-71085-9
pmc: PMC13035902
pii: 10.1038/s41467-026-71085-9