Anti-Tumour Immunity Relies on Targeting Tissue Homeostasis Through Monocyte-Driven Responses Rather Than Direct Tumour Cytotoxicity.

Abstract

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear. METHODS: In a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumour inhibition upon dietary correction. RESULTS: Carcinogenesis begins during MAFLD, with tumour cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to the turnover of liver cells but do not primarily target the tumour. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response-not merely immune activation-dictates whether tumours grow or regress, emphasising the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming. CONCLUSION: These findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumour-hostile microenvironment, whereas tumour-directed approaches fail to remodel the TME. This underscores the need for tissue remodelling strategies in cancer prevention and treatment.