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

Metabolic dysfunction–associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear. In a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumor inhibition upon dietary correction. Carcinogenesis begins during MAFLD, with tumor 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 turnover of liver cells but do not primarily target the tumor. 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 tumors grow or regress, emphasizing 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. 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 tumor-hostile microenvironment, whereas tumor-directed approaches fail to remodel the TME. This underscores the need for tissue remodeling strategies in cancer prevention and treatment. Our study challenges the traditional view that the liver is purely tolerant to immune responses, revealing that it actively regulates immunity to maintain tissue health. We found that liver cancer (HCC) begins during fatty liver disease (MAFLD) but can be halted if immune cells—especially monocytes—restore tissue integrity. Instead of focusing solely on killing tumors, effective immunotherapy should harness the body’s natural ability to repair the liver, creating an environment where cancer cannot thrive. This discovery paves the way for innovative treatments that promote immune-driven tissue regeneration as a strategy for cancer prevention and therapy.