– PT-129 is a RPOTAC degrader that targets the G3BP1/2NTF2 domain (protein-RNA interaction site), facilitating the breakdown of intracellular stress granules. It prevents the formation of stress granules in stressed cells and deconstructs existing ones, thereby disrupting ATF4 transmission and inhibiting cancer cell proliferation. Stress granules (SGs) are membraneless cytoplasmic compartments formed under stress, which aid in the transfer of ATF4 from fibroblasts to tumor cells, promoting fibroblast-related tumor growth. G3BP1/2 serve as central proteins in the SG network, and inhibiting them may reduce the stress resilience of cancer cells within the tumor microenvironment. PT-129 consists of a target protein ligand (red part) G3BP1/2-Targeting ligand-1, an E3 ligase ligand (blue part) Thalidomide 4-fluoride, and a PROTAC linker (black part) Amino-PEG3-C2-acid; the E3 ligase ligand and linker form the complex Thalidomide-NH-PEG3-propionic acid.