Abstract Despite the overall success of T-cell based immunotherapies, the number of patients that benefit is still lower than expected. Invariant Natural Killer T cells (iNKTs) offer an alternative and appealing therapeutic platform owing to their intrinsic features and independence from MHC restriction. In two mouse models, mirroring prostate or colon cancer, iNKTs play strikingly opposite roles, either promoting a TH1-skewed anti-tumor response, or fostering tumor progression with TR1-oriented status. The tepid results of iNKT cell-based therapies could reflect a thus far unappreciated plastic conversion of inflammatory iNKTs into regulatory NKT10 within the tumor’s microenvironment. This study aims to elucidate the occurrence and the dynamics of the inflammatory-to-regulatory iNKT cell plasticity in solid tumors, to clarify the environmental cues triggering their conversion and the molecular mechanisms that govern it. By employing innovative multi-cytokine reporter and fate mapping mice, we reliably detected iNKTs actively switching from producing IFNγ (exNKT1) to producing IL10, in the context of colon polyposis. Further analyses aim to unravel the molecular mechanisms of iNKT cell plasticity and to investigate the contribution of the tumor-specific microbial component. The currently incomplete understanding of iNKT cell plasticity is dampening the appropriate use of these powerful cells in therapeutic settings. As such, clinical protocols employing iNKTs for treating cancer have so far achieved only modest results. By addressing the molecular mechanisms underlying NKT10 conversion, we are likely to find pathways that can be targeted to fully unleash the anti-tumor power of these innate-like T cells in immunotherapy.