Tabriz University of Medical Sciences Pharmaceutical Sciences 1735-403X 31 1 2025 01 05 A DR4, DR5 Targeting Conjugated TRAIL Treatment for Colorectal Carcinogenesis: A Way to Future? 3 21 10.34172/PS.024.40334 EN Parikshit Roychowdhury https://orcid.org/0000-0002-3248-6645 Indhumathi Thirugnanasambandham https://orcid.org/0000-0002-9738-0139 Anindita De Mirunalini Gobinath Samanwita Khanra Veera Venkata Satyanarayana Reddy Karri https://orcid.org/0000-0003-2057-3423 Nihar Ranjan Bhuyan Gowthamrajan Kuppusamy https://orcid.org/0000-0001-9252-8926 REVIEW 10.34172/PS.024.40334 2024 03 24 2024 09 23 TRAIL or tumor necrosis factor-related apoptosis-inducing ligand has been one of the major frontiers for the chemotherapeutic approach to treating carcinogenesis. Despite the emergence of TRAIL resistance cancer cell lines, it has been extensively studied for its unique property to induce apoptosis and provide specificity to any other conjugated chemotherapeutic agent. TRIAL highly reduces the dose and increases specific and targeted action against the cancer cells. It is a specific agonist for the death receptors DR4 and DR5 present on the cancer cell surface. Normal cells have more expression of decoy type of death receptors, which makes the use of TRAIL safer for regular cells. The TRAIL-drug conjugate systems have been under the radar due to their possible high synergistic potential and may open the door for the future cancer-specific targeted treatment frontier. This current study was conducted with a particular aim to provide a concise and simple amalgamation of current scenarios of different conjugations of this molecule along with various other molecules, RNAs, ligands, and anticancer drugs. Along with possible delivery systems of TRIAL that can have a significant future and the promise that is held by this particular way of cancer combinational chemotherapy with special interest in colorectal cancer.