Plasticity and antigen presentation by group 3 innate lymphoid cells in colorectal cancer.

Colorectal cancer (CRC) develops within a mucosal ecosystem where the microbiota, epithelial barrier, and group 3 innate lymphoid cells (ILC3) jointly shape immune tone. ILC3 plasticity spans both tissue-protective and inflammatory states, and MHC II-dependent antigen presentation-like activity of ILC3 is associated with microbiota-directed CD4+ T cell and IgA responses. In CRC, chronic inflammation and dysbiosis drive a shift toward barrier-damaging ILC3 programs, attenuate epithelial antimicrobial defenses, and defocus microbiota-directed immunity. These alterations correlate with more aggressive tumor behavior and poorer responses to immune checkpoint therapy. We integrate this evidence into a feed-forward model in which impaired crosstalk among ILC3, the epithelium, and the microbiota promotes barrier weakening, inflammatory amplification, and tumor progression. Within this framework, we propose biomarker panels that capture ILC3 state, barrier integrity, and DEFB1 expression, together with therapeutic strategies targeting cytokine pathways, metabolism, microbiota structure, and immune checkpoints.