Fever Inspiration: Precision Engineering for Safe and Systemic Immunotherapy

Fever, a conserved physiological response, orchestrates robust immunomodulation with significant therapeutic potential. Engineered fever therapy (EFT) leverages this mechanism to activate systemic immune response, emerging as a transformative adjuvant strategy for disease management, particularly in oncology. However, achieving precise and safe EFT remains challenging, largely due to unpredictable temperature fluctuations and inconsistent immune responses. To address these limitations, thermal immunotherapy integrates precision thermal modulation with nanotechnology, enabling targeted induction of fever-range temperatures (38.5-40 °C) within tumor sites. Building upon physiological fever mechanisms and precision bioengineering, controllable EFT establishes a new paradigm with three core principles: i) precise fever induction with input and process control, ii) quantitative reprogramming of immune pathways, and iii) enhanced safety through optimized fever dynamics. This review comprehensively summarizes the molecular and physiological underpinnings of fever, evaluates its therapeutic potential in disease management, and presents recent progress in thermal immunotherapy and the EFT. Furthermore, future perspectives for controllable EFT are discussed and critically assessed, along with its opportunities and main challenges for clinical translation in precision oncology.