Nanomedicines　with　photodynamic　therapy　and　reactive　oxygen　species　(ROS)-triggered　drug　release　capabilities　are　promising　for　cancer　therapy.　However,　most　of　the　nanomedicines　based　on　ROS-responsive　nanocarriers　still　suffer　from　serious　ROS　consumption　during　the　triggered　drug　release　process.　Herein,　a　photodynamic-chemodynamic　cascade　strategy　for　the　design　of　drug　delivery　nanosystem　is　proposed.　A　doxorubicin　hydrochloride-loaded　ROS-responsive　polymersome　(DOX-RPS)　is　prepared　via　the　self-assembly　of　amphiphilic　poly(ethylene　glycol)-poly(linoleic　acid)　and　poly(ethylene　glycol)-(2-(1-hexyloxyethyl)-2-devinyl　pyropheophorbide-α)-iron　chelate　(PEG-HPPH-Fe).　The　RPS　can　effectively　deliver　a　drug　to　tumor　site　through　passive　targeting　effect.　Upon　laser　irradiation,　the　photosensitizer　HPPH　can　efficiently　generate　ROS,　which　further　causes　in　situ　oxidation　of　linoleic　acid　chain　and　subsequent　RPS　structural　destruction,　permitting　triggered　drug　release.　Intriguingly,　catalyzed　by　HPPH-Fe,　ROS　will　be　regenerated　from　linoleic　acid　peroxide　through　a　chemodynamic　process.　Therefore,　ROS-triggered　drug　release　can　be　achieved　without　ROS　over-consumption.　The　in　vitro　and　in　vivo　results　confirmed　ROS　generation,　triggered　drug　release　behavior,　and　potent　antitumor　effect　of　the　DOX-RPS.　This　photodynamic-chemodynamic　cascade　strategy　provides　a　promising　approach　for　enhanced　combination　therapy.　©　2021　The　Authors.　Advanced　Science　published　by　Wiley-VCH　GmbH