While previous studies attributed HER2-targeted drug resistance to ERBB2 mutations or downstream pathway activation, this case suggests that in ERBB2 amplified tumors, ADC-immune checkpoint inhibitor combinations may reverse resistance through: (1) T-DXd-induced immunogenic cell death enhancing PD-1 inhibitor efficacy; (2) Toripalimab-mediated reversal of T-cell exhaustion and tumor microenvironment modulation. This evidence concerns the gene ERBB2 and neoplasm.