Identifying the therapeutic potential of Niclosamide in overcoming IFN-gamma dependent cancer immune evasion in the Tumor Microenvironment

Although IFN-γ activates both STAT1 and STAT3, how these pathways interact to regulate immune evasion under hypoxia remains unclear. Using the MC38 murine colorectal cancer model and T cell–tumor spheroid co-culture assays, we examined how IFN-γ signaling through STAT1 and STAT3 regulates PD-L1 expression, CSC plasticity, and cytotoxic T cell function under normoxic and hypoxic conditions.

Pharmacologic inhibitors and siRNA-mediated knockdown were used to dissect pathway function, and Niclosamide, an FDA-approved anthelmintic, was evaluated as a dual STAT1/STAT3 inhibitor. We found that IFN-γ primarily induced PD-L1 expression through STAT1 activation, whereas CSC plasticity was associated with STAT3 signaling. STAT1 and STAT3 displayed reciprocal regulation—blocking one enhanced activation of the other.