Apo2L/TRAIL is a member of the TNF superfamily that induces apoptosis by binding to death receptors (DR4 and DR5) and decoy receptors (DcR1 and DcR2). It selectively kills transformed cells but not normal cells, making it a potential cancer therapy. Apo2L/TRAIL forms a trimeric complex that binds to three receptors, with a zinc atom essential for its function. The ligand can be delivered as a soluble protein, but its effectiveness depends on proper preparation to avoid toxicity. Apo2L/TRAIL activates the DISC, leading to caspase-8 and caspase-9 activation, which triggers apoptosis. The Bcl-2 family, including Bax, plays a critical role in mitochondrial pathways that contribute to Apo2L/TRAIL-induced apoptosis. In some cells, Apo2L/TRAIL can bypass the mitochondrial pathway by activating caspase-8 directly. The Bcl-2 family members Bcl-2 and Bcl-XL can inhibit Apo2L/TRAIL-induced apoptosis by blocking mitochondrial changes. However, in some cases, Apo2L/TRAIL can still induce apoptosis through other pathways. Apo2L/TRAIL also interacts with other signaling pathways, such as NF-κB, p53, and kinases, which can modulate its activity. In addition to apoptosis, Apo2L/TRAIL has non-apoptotic functions, such as immune surveillance and inhibiting autoimmune inflammation. It is expressed in various cell types, including NK cells, and plays a role in preventing liver metastasis and fibrosarcoma development. Apo2L/TRAIL is effective against multiple cancer types, including leukemia, multiple myeloma, and solid tumors. It can be used in combination with chemotherapy or radiation to enhance antitumor effects. Recombinant versions of Apo2L/TRAIL have been developed for clinical use, with optimized formulations that minimize toxicity to normal cells. However, certain versions of Apo2L/TRAIL can induce apoptosis in normal cells, such as hepatocytes, highlighting the need for careful preclinical evaluation. Apo2L/TRAIL has significant therapeutic potential as a cancer treatment, particularly in cancers resistant to conventional therapies. Its ability to induce apoptosis in cancer cells while sparing normal cells makes it an attractive candidate for further development. However, understanding the mechanisms of resistance and optimizing its delivery are critical for its successful application in clinical settings.Apo2L/TRAIL is a member of the TNF superfamily that induces apoptosis by binding to death receptors (DR4 and DR5) and decoy receptors (DcR1 and DcR2). It selectively kills transformed cells but not normal cells, making it a potential cancer therapy. Apo2L/TRAIL forms a trimeric complex that binds to three receptors, with a zinc atom essential for its function. The ligand can be delivered as a soluble protein, but its effectiveness depends on proper preparation to avoid toxicity. Apo2L/TRAIL activates the DISC, leading to caspase-8 and caspase-9 activation, which triggers apoptosis. The Bcl-2 family, including Bax, plays a critical role in mitochondrial pathways that contribute to Apo2L/TRAIL-induced apoptosis. In some cells, Apo2L/TRAIL can bypass the mitochondrial pathway by activating caspase-8 directly. The Bcl-2 family members Bcl-2 and Bcl-XL can inhibit Apo2L/TRAIL-induced apoptosis by blocking mitochondrial changes. However, in some cases, Apo2L/TRAIL can still induce apoptosis through other pathways. Apo2L/TRAIL also interacts with other signaling pathways, such as NF-κB, p53, and kinases, which can modulate its activity. In addition to apoptosis, Apo2L/TRAIL has non-apoptotic functions, such as immune surveillance and inhibiting autoimmune inflammation. It is expressed in various cell types, including NK cells, and plays a role in preventing liver metastasis and fibrosarcoma development. Apo2L/TRAIL is effective against multiple cancer types, including leukemia, multiple myeloma, and solid tumors. It can be used in combination with chemotherapy or radiation to enhance antitumor effects. Recombinant versions of Apo2L/TRAIL have been developed for clinical use, with optimized formulations that minimize toxicity to normal cells. However, certain versions of Apo2L/TRAIL can induce apoptosis in normal cells, such as hepatocytes, highlighting the need for careful preclinical evaluation. Apo2L/TRAIL has significant therapeutic potential as a cancer treatment, particularly in cancers resistant to conventional therapies. Its ability to induce apoptosis in cancer cells while sparing normal cells makes it an attractive candidate for further development. However, understanding the mechanisms of resistance and optimizing its delivery are critical for its successful application in clinical settings.