The　rational　design　of　nanoplatforms　to　bypass　reticuloendothelial　system　(RES)　clearance,　enhance　spatiotemporal　controllability,　and　boost　host　immune　responses　to　achieve　synergized　tumor-targeted　therapeutic　purpose　is　highly　desired.　Herein,　a　biomimetic　nanosystem　is　developed　for　tumor-targeted　in　situ　delivery　of　singlet　oxygen　(1O2)　and　carbon　monoxide　(CO)　in　response　to　exogenous　stimulus　ultrasound　(US)　and　endogenous　stimulus　hydrogen　peroxide　(H2O2)　in　tumor　microenvironment,　respectively.　Taking　advantages　of　tumor　homing　and　RES　evasion　abilities　of　the　macrophage　membrane　coating,　our　designed　nanosystem　shows　excellent　accumulation　at　the　tumor　site　and　effective　suppression　of　tumor　growth　through　US/H2O2-generated　1O2　and　CO　to　induce　cell　apoptosis　and　mitochondrial　dysfunction.　Furthermore,　our　nanosystem　can　induce　significant　tumor　immunogenic　death　by　1O2/CO　therapy,　then　can　achieve　effective　immune　responses　and　long-term　immune　memory　through　the　combination　of　indoleamin　2,3-dioxygenase　(IDO)　signal　blocking　to　effectively　against　tumor　rechallenge　and　prevent　lung　metastasis.　Taken　together,　the　here-presented　therapeutic　strategy　based　on　sonodynamic/CO　therapy　and　IDO　signaling　inhibition　might　provide　a　promising　perspective　for　synergistically　treating　cancer　in　future　clinical　translations.　©　2020　American　Chemical　Society.