1. Introduction
In recent decades, precision therapy has emerged as a prominent approach in clinical cancer treatment. Alongside traditional methods such as surgery, chemotherapy, and radiotherapy, novel treatments like targeted therapy, interventional therapy, and immunotherapy have expanded the options available to healthcare professionals.[1-5] A promising development in cancer treatment is photothermal therapy (PTT), which is a non-invasive and highly targeted treatment method.[6-10] When exposed to an external light source, the photothermal agents (PTAs) injected and accumulated in lesion tissues will convert light energy into heat energy to effectively kill the diseased cells such as tumor cells. PTT offers several advantages, including high selectivity, minimal systemic toxic side effects, short treatment durations (typically just a few minutes), and noticeable therapeutic effects. Conventional PTT often requires high local temperatures exceed 50 ℃, which may also inadvertently damage surrounding healthy tissue, leading to challenges in achieving optimal treatment outcomes.[11-14] Besides, the suboptimal effectiveness of conventional PTT can be attributed to various factors including heterogeneous PTA distribution (PTAs may not be evenly distributed within cancer cells), limited light penetration (The depth to which the laser light can penetrate is restricted, making it less effective for deep-seated tumors), and difficulty in temperature control (Precisely controlling the photothermal process is challenging and may lead to overheating, causing severe side effects, including inflammation, immune system evasion, metastasis, and harm to normal tissues surrounding the tumor).
To address these shortcomings, researchers have been exploring the potential of mild PTT (MPTT, operating at lower temperatures, typically below 45 ℃), which has the potential to significantly improve treatment efficacy, reduce drug dosage, lower hyperthermia temperatures, and minimize damage to healthy tissues.[15-18] In cancer therapy, one avenue of research involves inhibiting the synthesis of heat shock proteins (HSPs) in tumor cells, which help to develop heat resistance.[19-21] By blocking HSPs expression, MPTT can kill tumor cells at lower temperatures without harming nearby healthy cells. Despite significant progress in MPTT, it remains primarily in the stages of basic and clinical research, and has not yet seen widespread clinical adoption due to several technical challenges. For instance, striking the right balance between hyperthermia and MPTT temperatures is crucial to avoid damaging normal tissues while maintaining treatment effectiveness. Besides, current clinical lasers have limited penetration depth, restricting their use to superficial tumors.[22-25] Therefore, choosing the suitable near-infrared (NIR) PTAs is significant for various biomedical applications, as some organic molecules have limited photothermal stability, while inorganic nanomaterials may pose potential toxicity risks.
In this review, we provide a comprehensive overview of the recent development of MPTT, emphasizing its mechanisms, the characteristics of commonly used NIR PTAs (both organic and inorganic materials), and the applications in biomedicine field (Scheme 1). Then, we address the key obstacles facing MPTT and propose the potential solutions, and explore the status of MPTT combined with other anti-tumor therapies. Specifically, we discuss the broader applications in areas such as anti-infection, obesity treatment, and vascular disease treatment. Finally, we look ahead to future research directions in MPTT, aiming to enhance its efficiency and safety while developing new strategies for high-efficiency MPTT.