Innovative strategies to boost photothermal therapy at mild temperature mediated by functional nanomaterials

Construction of photothermal therapy (PTT) at mild temperature through regulating heat shock proteins expression, autophagy level, free radical generation and organelle targeting, along with the combination of mild-temperature PTT with other treatment modalities to yield the remarkable superadditive effect. [Display omitted] •The mild temperature threshold is firstly elucidated and the possible methods to decrease the mild temperature threshold are provided.•The representative examples that have been or possibly been used in constructing mild-temperature PTT system to combat cancer are systematically summarized.•The challenges and possible development for enhanced mild-temperature PTT are highlighted. The last few years have witnessed explosive growth in the design and development of various photothermal agents (PTAs) to realize phtothermal therapy (PTT) for eradicating solid tumors. Nevertheless, the therapeutic efficacy of PTT is still restricted by several obstacles, especially the thermotolerance of tumors, which might potentially induce inflammatory disease, damage normal organs, or even lead to tumor recurrence. Exploitation of innovative strategies to enhance PTT at mild temperature is thus the key determinant toward successful clinical use of PTT. In this review, we dissect the cell death mechanism triggered by PTT at different temperature, indicating that enhancing apoptosis pathway is favorable for PTT at mild temperature. The recent advances in the construction of mild-temperature PTT through regulating heat shock proteins expression, autophagy level, free radical generation and organelle targeting to overcome tumor thermotolerance are susequently concluded, along with the excellent and representative examples of combining mild-temperature PTT with other therapies (i.e. photodynamic therapy, chemodynamic therapy, starvation therapy and gas therapy), which exhibits the remarkable superadditive effect. Furthermore, the key scientific and technical challenges for mild-temperature PTT are also discussed to accelerate clinical translation.