Solid tumors are regarded as complex evolving systems rather than simple diseases. Self-adaptive synthetic therapeutics are required to cope with the challenges of entire tumors; however, limitations in accurate positioning and destruction of hypoxic niches seriously hinder complete tumor eradication. In this study, we engineer a molecular nanoassembly of sorafenib and a hypoxia-sensitive cyanine probe (CNO) to facilitate periphery/center synergistic cancer therapies. The self-adaptive nanoassembly with cascade drug release features not only effectively kills the peripheral tumor cells in normoxic rims but precisely illuminates hypoxic niches following the reduction of CNO by nitroreductase. More important, CNO is found to synergistically induce tumor ferroptosis with sorafenib via nicotinamide adenine dinucleotide phosphate (NADPH) depletion in hypoxic niches. As expected, the engineered nanoassembly demonstrates self-adaptive hypoxic illumination and periphery/center synergetic tumor eradication in colon and breast cancer BALB/c mouse xenograft models. This study advances turn-on hypoxia illumination and chemo-ferroptosis toward clinical applicability.