Timing matters: how mechanism-guided sequencing shapes the efficacy of radiotherapy-immunotherapy combinations : A systematic review.

PURPOSE: The combination of radiotherapy (RT) and immunotherapy has emerged as a central strategy in modern oncology, yet clinical outcomes remain highly variable. This variability is critically influenced by timing, including sequencing, interval, and temporal alignment with immune dynamics. We performed a systematic review to evaluate how mechanism-guided timing of RT relative to different immunotherapy classes shapes antitumor efficacy.

METHODS

A systematic literature search was conducted in PubMed, Embase, and Web of Science for studies published between 2009 and January 2026 evaluating RT-immunotherapy combinations with explicit timing or sequencing analysis. Preclinical and clinical studies reporting immune mechanisms, systemic immune responses, or efficacy outcomes were included. Data were extracted on immunotherapy class, RT regimen, sequencing strategy, and outcomes. Risk of bias was assessed using design-appropriate tools.

RESULTS

A total of 84 studies met inclusion criteria: 56 preclinical and 28 clinical, including four randomized controlled trials. Timing emerged as a critical biological determinant of synergy. Radiotherapy induced a temporally dynamic immune response encompassing immunogenic cell death, innate immune activation, T‑cell priming, and adaptive immune resistance. Optimal sequencing was mechanism-dependent: Cytotoxic T‑lymphocyte-associated protein 4 (CTLA-4) blockade was most effective before or concomitantly with RT; programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors performed best after RT, during peak T‑cell infiltration and checkpoint upregulation; co-stimulatory agonists showed optimal activity shortly after RT; and innate immune activators required immediate post-RT administration. Emerging evidence suggests circadian timing may further modulate efficacy.

CONCLUSION

Timing is not a logistical variable but a central biological component of RT-immunotherapy combinations. A mechanism-guided temporal framework substantially influences immune responses and therapeutic outcomes, representing a low-cost, high-impact optimization strategy. Circadian considerations remain compelling but require validation in prospective trials.