Cancer continues to be a significant global public health concern, ranking as the second leading cause of death in China [1]. Chemotherapy is one of the main means of anti-tumor treatment, but it often causes treatment-related neurological side effects while achieving therapeutic effects. One of the most prevalent and debilitating adverse outcomes of chemotherapy is chemotherapy-induced peripheral neuropathy (CIPN). This condition primarily affects the sensory and motor peripheral nerves, leading to a range of debilitating symptoms [2], [3]. Notably, these symptoms may persist for a long time after chemotherapy, severely affecting patients' quality of life, increasing psychological distress, and decreasing adherence to subsequent chemotherapy cycles [4]. According to the American Society of Clinical Oncology (ASCO) guidelines, duloxetine is recommended (moderately) for neuropathic pain associated to CIPN [3]. However, the variability in patient responses to this treatment limits its broad clinical applicability. Therefore, there remains a pressing need for the identification of alternative, safe, and effective therapies to address this critical gap in cancer care.

Paclitaxel is among the most frequently prescribed chemotherapeutic agents, exerting its antineoplastic activity by stabilizing microtubules, disrupting the dynamic equilibrium of polymerization and depolymerization, and thereby arresting cells in the G₂/M phase [5]. This mechanism effectively inhibits tumor cell proliferation and induces apoptosis. Paclitaxel is commonly employed as a first-line treatment for a variety of solid malignancies, including those of the breast, ovary, non-small cell lung, and prostate. However, paclitaxel-induced peripheral neuropathy (PIPN) frequently arises during treatment, presenting with a spectrum of sensory, motor, and autonomic dysfunction [6]. Sensory neuropathy typically appears first in the distal extremities in a characteristic “glove-and-stocking” distribution, with symptoms such as numbness, tingling, altered tactile perception, and dysregulated thermal sensitivity [7], [8]. The pathogenesis of PIPN is multifactorial, encompassing disrupted axonal transport and degeneration, mitochondrial dysfunction with resultant oxidative stress, ion channel dysregulation, and neuroinflammatory processes driven by immune activation [9], [10], [11], [12], [13]. These convergent mechanisms contribute to structural and functional neuronal damage, yet no preventive or reparative therapy beyond symptomatic management currently exists.

Photobiomodulation (PBM), previously known as low-level laser therapy, involves the use of non-ionizing light at specific wavelengths (typically ranging from 600 to 1100 nm) to induce various biological effects on tissues [14]. Through photochemical reactions, photons are absorbed by intracellular chromophores, which trigger conformational changes that enhance mitochondrial respiration and adenosine triphosphate (ATP) synthesis [15]. The primary mechanisms of PBM include the enhancement of mitochondrial enzyme activity, stimulation of cellular metabolism, modulation of reactive oxygen species (ROS) to strengthen antioxidant defenses, activation of ion channels and associated signaling pathways, as well as the promotion of cellular proliferation [16], [17], [18], [19]. Since the 1980s, extensive in vitro and in vivo research has explored PBM as a therapeutic modality for nervous system disorders. In neuronal cultures, PBM has been shown to facilitate axonal regeneration, synaptogenesis, and Schwann cell proliferation [20], [21]. By optimizing mitochondrial oxidative metabolism, PBM accelerates neuronal recovery following injury, while concurrently attenuating neuroinflammation through modulation of pro-inflammatory signaling cascades [22], [23]. Moreover, PBM increases the expression of neurotrophic factors and associated functional proteins via activation of intracellular pathways including MAPK/ERK and PI3K/Akt [24], [25], [26]. Currently, PBM has made significant progress in the treatment of multiple clinical diseases with its advantages of non-invasiveness, no toxic side effects and multi-target regulation [27], [28], [29]. As an emerging physical therapy, PBM is expected to provide burgeoning non-pharmacological intervention for managing CIPN in clinical settings, which deserves rigorous scientific research.

The objective of this study is to assess the therapeutic potential of near-infrared PBM in treating CIPN and to investigate the underlying molecular mechanisms involved. Specifically, we will explore the multifaceted effects of PBM, including improving paresthesia, promoting nerve regeneration, regulating inflammatory processes, attenuating oxidative stress, and inhibiting apoptotic pathways, thereby clarifying its potential as a safe and effective intervention to alleviate CIPN-related adverse reactions in clinical chemotherapy patients.