Collectively, our results reveal that the SH003 and DTX combination effectively targets both tumor-intrinsic signaling pathways and immune-mediated mechanisms, providing a dual approach to overcoming anti-PD1 resistance through simultaneous modulation of the EGFR/STAT3/PD-L1 axis and enhancement of immune-mediated cytotoxicity in the TME. The gene discussed is STAT3; the disease is neoplasm.