ICAM1 and neoplasm: Mechanistically, we discovered that combination with DAC generates five major advantages for improving the in vivo efficacy of I1‐DXd as follows: (1) I1‐DXd monotherapy reprogrammed TME to boost anti‐tumor immunity in synergy with DAC; (2) DAC upregulates ICAM1 expression on melanoma cell surface via dsDNA accumulation; (3) DAC increases the cellular internalization of ICAM1‐ADC; (4) DAC sensitizes melanoma tumors to I1‐DXd treatment via promoting apoptosis; (5) DAC enhances tumor penetration of I1‐DXd in vivo.