Photothermal　therapy　(PTT)　exhibits　an　excellent　therapeutic　effect　in　cancer　treatment,　but　some　cancers　are　still　facing　rapid　recurrence　due　to　the　presence　of　heat-resistant　cells,　which　express　heat　shock　proteins　(HSP)　to　defend　against　hyperthermia.　Inspired　by　optogenetics,　we　firstly　designed　a　caged　TNF-related　apoptosis-inducing　ligand　(TRAIL)　expressing　plasmid　under　HSP70　protomer　(HSP70-TRAIL)　as　the　thermal-activated　gene　therapy　agent　to　induce　the　apoptosis　of　heat　resistant　cells.　Then,　the　caged　HSP70-TRAIL　was　decorated　on　the　surface　of　the　photothermal　agent　(semiconducting　nanoparticles,　SPNs)　through　electrostatic　adsorption　to　obtain　SPN@HSP70-TRAIL-GFP　(SPNHT).　Under　1064　nm　near-infrared　second　region　(NIR-II)　laser　irradiation,　the　SPNHT　acted　as　an　emerging　photothermal　agent　for　PTT.　Importantly,　the　caged　HSP70-TRAIL　could　be　further　activated　by　PTT　to　express　TRAIL　on　demand　to　concurrently　kill　survival　cells　for　overcoming　the　problem　of　tumor　recurrence　after　PTT.　Bothin　vitroandin　vivostudies　demonstrated　that　the　SPNHT　nano-system　with　the　ability　of　NIR-II　photothermal-triggered　TRAILin　situexpression　possessed　an　admirable　synergistic　anti-cancer　efficacy　for　HCC.　This　work　offers　new　tactics　for　effective　treatment　of　cancer,　which　showed　a　great　significance　for　reducing　the　rate　of　cancer　recurrence　after　PTT　treatment.　©　The　Royal　Society　of　Chemistry　2021.