Tissue-penetration-depth-independent self-luminescence is highly expected to perform photoisomerization-related bioapplications in vivo to overcome the limitation of shallow tissue-penetration from external photoexcitation. However, it remains extremely challenging because of lacking a target-specific high-intensity self-luminescence to precisely and effectively drive the photoisomerization. Here, we first report a target-specific tissue-depth-independent photoisomerization in vivo by developing a target-specific initiated and in situ-enhanced chemiluminescence (one of self-luminescence) strategy that overcomes the limitation of lacking target-specific high-intensity self-luminescence. Considering that photoisomerization shows boundless glamour in drug-controlled release for disease-specific chemotherapy, we demonstrated applicability of our strategy to apply it in tumor-specific self-luminescence-controlled drug chemotherapy. Specifically, a chemiluminescence substrate and chemiluminescence fluorophore (antitumor drug, CPT) were co-encapsulated in host-guest carriers composed of cyclodextrin and the photoisomerization molecule azobenzene. Tumor-specific H2O2-induced chemiluminescence preliminarily isomerizes azobenzene, triggering the partial dissociation of host-guest carriers and CPT release. Particularly, the initially released CPT again functions as a chemiluminescence enhancer to achieve in situ enhanced chemiluminescence, assuring target-specific enhanced isomerization and CPT release. With high tumor-inhibition-rate (73%) and no obvious therapy-side-effect in vivo indicates the good efficiency and target-specificity of our chemiluminescence-driven photoisomerization. Although we only demonstrated one example of a photoisomerization-related bioapplication, namely photoisomerization-controlled drug chemotherapy, our work provides guidelines to design various target-specific tissue-depth-independent photoisomerization for bioapplications.