The quest to maximize therapeutic efficiency in cancer treatment requires innovative delivery nanoplatforms capable of employing different modules simultaneously. Combination therapy has proven to be one of the best anticancer strategies so far. Herein, we developed a lipid-encapsulated nanoplatform that combines chemotherapy with photoresponsive gas therapy for colon cancer treatment. Carbon monoxide releasing molecule (CORM) and α-tocopheryl succinate (α-TOS) were co-loaded into the lipid layer with core-shell upconversion nanoparticles (UCNPs), which converted 808 nm lights to 360 nm photons for CO release at the tumor site. This nanomedicine (Lipid/UCNP/CORM/α-TOS/FA: LUCTF) possessed enhanced targeting ability, and light-triggered CO release ability for synergistic apoptosis of HCT116 cells via enhanced ROS generation and mitochondria membrane breaking. In vivo data confirmed the significantly enhanced therapeutic efficacy of LUCTF without any significant biosafety issues after intravenous administration. Thus, nanomedicine LUCTF represents a novel way for efficient cancer therapy via combining locally released CO and a compatible chemotherapeutic agent (α-TOS).