KRAS mutations drive multiple cancers, yet effective targeted therapies remain elusive. Given the heightened macropinocytosis in KRAS-mutant tumors, we leveraged this feature to enhance drug delivery using MPD1, an albumin-binding, caspase-3 cleavable peptide-doxorubicin conjugate. MPD1 enters tumor cells via macropinocytosis, triggering apoptosis and self-amplifying drug release through caspase-3 activation. We discovered that DNA-PK inhibitor (DNA-PKi) selectively enhances albumin uptake in KRAS-mutant cancers by activating AMPK, an energy sensor inducing nutrient scavenging. This synergistic effect increased MPD1 accumulation in KRAS-mutant tumors, overcoming tumor heterogeneity. Combination therapy of MPD1 and DNA-PKi achieved 100% complete remission in KRAS-mutant TNBC xenografts, highlighting its clinical potential. Our findings reveal a dual role of DNA-PKi: blocking DNA repair and enhancing macropinocytosis for drug delivery. This strategy provides a promising approach for treating PI3K-activated cancers, including KRAS-mutant tumors.