The paradigm-shifting roles of caspase-3 in cancer: from death towards resuscitation.

In Taoism, all entities in the universe embody two complementary forces—Yin and Yang—that are oppositional yet unified. Their subtle interplay governs the direction and progression of events. Caspase-3 is renowned for mediating apoptosis, whereas accumulating evidence has revealed its role in stimulating compensatory proliferation. In cancer, while caspase-3 activation is traditionally regarded as tumor-suppressive due to its ability to induce cell death, particularly apoptosis, increasing evidence has highlighted its tumor-supportive functions. These dual roles of caspase-3 exemplify the Taoist principle of “Yin and Yang”. This review begins by outlining the canonical apoptotic role of caspase-3, and then discusses its non-apoptotic roles across diverse pathophysiological contexts, with specific emphasis on its tumor-supportive mechanisms in: tumor repopulation, tumor angiogenesis, tumorigenesis, tumor migration, invasion and metastasis, cancer stem cell maintenance, therapy resistance, and tumor immune response. The emerging tumor-promoting functions of caspase-3 challenge the conventional therapeutic paradigm of activating caspase-3. Instead, caspase-3 inhibition may represent a promising alternative strategy for cancer treatment.