KEY POINTS
- This systematic review searched PubMed/MEDLINE, Embase, and Web of Science for studies published from January 2009 to January 2026 evaluating radiotherapy-immunotherapy combinations with explicit timing or sequencing analysis.
- 84 studies met inclusion criteria: 56 preclinical studies and 28 clinical studies, including 4 randomized controlled trials.
- The review frames radiotherapy as a temporally dynamic immune intervention, with immunogenic cell death, cGAS-STING activation, T-cell priming, effector expansion, and later adaptive immune resistance.
- Optimal sequencing differed by immunotherapy class: CTLA-4 blockade before or concomitant with radiotherapy; PD-1/PD-L1 blockade early after radiotherapy; OX40/co-stimulatory agonists shortly after radiotherapy; and TLR/STING agonists immediately after radiotherapy, with STING agonists proposed within 24–72 hours.
- Circadian timing was discussed as a possible optimization layer, but the review cautioned that LungTIME-C01 findings remain under investigation and should not yet drive clinical implementation.
CLINICAL TAKEAWAY
Timing should be treated as a biological variable in radiotherapy-immunotherapy trial design, not as a scheduling afterthought. The review offers a useful mechanism-based framework for choosing whether immunotherapy should come before, during, or after radiotherapy depending on the agent class. But the evidence remains heterogeneous, largely preclinical, and not strong enough to define practice-changing schedules across tumor types.