Atomic degradation: chemical design strategies and immunotherapeutic mechanisms of radio-PROTACs

Abstract

Convergence of Proteolysis Targeting Chimeras (PROTACs) and Targeted Alpha Therapy (TAT) is proposed here as a novel pharmacological frontier in precision oncology, aimed at overcoming mutually exclusive resistance mechanisms of each parent modality. While PROTACs provide catalytic ablation of oncoproteins, their efficacy is often limited by E3 ligase alterations. Conversely, TAT deliver high-LET radiation but lack intrinsic signaling modulation. This study critically examines the design of Radio-PROTACs, heterotrifunctional constructs that integrate a macrocyclic chelator within the linker region of a degrader. We postulate a “Hot Linker” strategy to balance chelation stability with the entropic requirements for ternary complex formation. A synchronized “Inflict-and-Disarm” mechanism is proposed: (i) Genomic Ablation via high-LET radiation, and (ii) Proteome Editing to degrade DDR proteins (e.g., RAD51, BRD4), thereby sensitizing cells to radioactive decay. Furthermore, we explore the potential for Radio-PROTACs to remodel tumor microenvironment by amplifying radiation-induced cGAS-STING activation while simultaneously degrading checkpoint proteins to overcome immune resistance. Despite the compelling therapeutic rationale, significant translational bottlenecks remain, including the permeability paradox, recoil effects, and the unvalidated temporal synchronization between degradation kinetics and isotopic decay. This work provides a stage-gated preclinical roadmap defining the essential experiments required to transition Radio-PROTACs from theoretical concept to therapeutic reality.