Combination of Radioligand Therapy and Immunotherapy: How to Make It Work in Clinic?

Combining external beam radiation therapy (EBRT) with immunotherapy showed promise pre-clinically by inducing immunogenic cell death (ICD) thus releasing damage-associated molecular patterns (DAMPs) and cytokines to activate the immune system. Clinical results, however, have often been disappointing. Radioligand therapy (RL), which uses targeted radionuclides to deliver cytotoxic radiation, offers advantages over EBRT by treating multiple tumors simultaneously. Combining RL with immunotherapy faces challenges, as prolonged radiation exposure can damage immune cells, and the "cross-fire" and "bystander" effects may harm incoming effector cells. Current RL therapies require multiple doses, further complicating immune cell viability. To optimize RL-immunotherapy combinations, timing is critical. Administering immunotherapy weeks after RL therapy may reduce radiation-induced immune cell damage. Additionally, selecting radionuclides with shorter half-lives could minimize immune cell toxicity while maintaining tumor-killing efficacy. Future RL therapies should prioritize radionuclides with optimal emission profiles and half-lives to enhance synergy with immunotherapy and improve clinical outcomes.