Tumor‐Regional Immune Microenvironment: A Critical Factor in the Design of Radiotherapy–Immunotherapy Combination Trials

Clinical trials combining radiotherapy (RT) with immune checkpoint blockade (ICB) have shown improved outcomes in only a fraction of patients, and optimal strategies for integrating these modalities remain under intense investigation. With a few exceptions, phase III combination trials have yielded disappointing results. This may be due to detrimental effects of RT on the tumor-regional immune microenvironment (TRIME), including tumor-draining lymph nodes (TDLNs) and intratumoral immune aggregates such as tertiary lymphoid structures. TDLNs are crucial for generating tumor-specific T cells, including progenitors of exhausted T cells. Intratumoral immune aggregates are hubs for immune cell interaction participating in induction or reactivation of antitumor immune responses. Understanding the biological role of the TRIME in RT/ICB-induced antitumor immunity is therefore essential for designing RT-immunotherapy combination trials. This review also highlights several potential strategies to optimize RT/ICB combination therapy. One approach involves modifying treatment schedules, for example, delaying RT to TDLNs until after ICB to allow effective immune priming. Another promising strategy is the integration of advanced imaging techniques into RT planning to improve precision and minimize radiation exposure to TDLNs. Applying unconventional RT with lower total dose or to selective areas may help preserve immune aggregates within tumors, potentially enhancing synergy with ICB. Another important approach is the use of dendritic cell agonists to boost the function of the TRIME. These approaches may help unlock the full therapeutic potential of RT/ICB combinations.