This review was conducted using a systematic approach to literature selection. We searched major databases including PubMed, Web of Science, and Scopus for articles published between 2000 and 2024. Keywords included “photobiomodulation,” “low-level light therapy,” “immunomodulation,” and specific terms related to immune cells and conditions. We included original research articles, systematic reviews, and meta-analyses Case reports and studies with fewer than 10 participants were excluded to ensure statistical robustnessminimum, Table 1. The minimum level of evidence for inclusion was set at Level 2 according to the Oxford Centre for Evidence-Based Medicine guidelines. Where The Oxford Centre for Evidence-Based Medicine (OCEBM) guidelines categorize evidence into levels based on its strength and reliability. Level 2 evidence is considered relatively strong and typically includes:

Level 2a: Systematic reviews of cohort studies (studies that follow groups of people over time to assess outcomes).

Level 2b: Individual cohort studies or low-quality randomized controlled trials (RCTs).

Level 2c: Outcomes research (studies that focus on the results of interventions in real-world settings).

Table 1 Summary of key clinical studies on photobiomodulation in immune-related conditions

In simpler terms, Level 2 evidence is based on well-designed studies that observe or compare groups of people, but it may not be as rigorous as Level 1 evidence, which includes high-quality randomized controlled trials or systematic reviews of such trials. By setting the minimum level of evidence at Level 2, the authors are indicating that they included studies with a reasonable degree of reliability, but not necessarily the highest level of evidence available.

Mechanisms of photobiomodulation-induced ImmunomodulationPhotobiomodulation at the cellular level

The fundamental mechanisms of photobiomodulation-induced immunomodulation begin at the cellular level, primarily through interactions with mitochondria, the powerhouses of the cell. When cells are exposed to light at specific wavelengths and intensities, photoreceptors within the mitochondrial electron transport chain, particularly cytochrome c oxidase, absorb the photons. This interaction triggers a cascade of events that ultimately lead to altered cellular function and signaling [5] Fig. 2.

Fig. 2

Showed photobiomodulation mechanism in both in-vivo and ex-vivo adopted from Salman, S., et al. 2023

Effects on mitochondrial function and ATP production

Photobiomodulation has been shown to increase the activity of cytochrome c oxidase, leading to enhanced electron flow through the respiratory chain. This results in increased proton gradient across the mitochondrial membrane and, consequently, elevated ATP production [6]. The boost in cellular energy availability has profound effects on various cellular processes, including those involved in immune responses. Specifically, PBM has been shown to enhance phagocytic activity (the ability of immune cells like macrophages and neutrophils to engulf and destroy pathogens), cytokine production (signaling molecules that regulate immune responses), and lymphocyte proliferation (the expansion of immune cells like T-cells and B-cells, which are critical for adaptive immunity). Additionally, PBM can modulate reactive oxygen species (ROS) production and nitric oxide (NO) release, both of which play key roles in immune regulation and inflammation.

de Freitas and Hamblin (2023) demonstrated that photobiomodulation can increase ATP production by up to 70% in certain cell types, providing the energy necessary for enhanced cellular activities such as cytokine production, phagocytosis, and cell proliferation [7]. This energetic boost is particularly crucial for immune cells, which often require rapid and energy-intensive responses to stimuli.

Modulation of reactive oxygen species (ROS)

Photobiomodulation has a biphasic effect on ROS production, depending on the dosage and cellular redox state. For instance, low-dose PBM (e.g., 5–10 J/cm²) has been shown to reduce excessive ROS levels in oxidative stress conditions, thereby protecting cells from damage and promoting cellular repair. This is supported by studies such as those by Chen et al. (2011), which demonstrated that PBM at low fluences reduces ROS in neurons exposed to oxidative stress. Conversely, higher doses of PBM (e.g., 20–50 J/cm²) can temporarily increase ROS production in healthy cells, which acts as a signaling mechanism to stimulate cellular proliferation, antioxidant defenses, and immune activation. This biphasic response is further illustrated in the work of Hamblin (2023), who highlighted that the cellular redox state and baseline ROS levels determine whether PBM will upregulate or downregulate ROS production. At lower doses, photobiomodulation tends to reduce excessive ROS levels in stressed or inflamed tissues, exerting an antioxidant effect. Conversely, at higher doses or in normal cellular conditions, photobiomodulation can induce a mild, transient increase in ROS [8].

This modulation of ROS levels plays a significant role in immune cell signaling and function. Low levels of ROS can act as signaling molecules, activating redox-sensitive transcription factors like NF-κB and AP-1, which are crucial in immune cell activation and cytokine production [9]. The ability of photobiomodulation to fine-tune ROS levels allows for precise modulation of immune cell behavior.

Impact on signaling pathways

The cellular changes induced by photobiomodulation lead to the activation or modulation of various signaling pathways that are critical in immune cell function and inflammatory responses.

NF-κB pathway modulation

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is a key regulator of inflammation and immune responses. Photobiomodulation has been shown to modulate this pathway in a context-dependent manner. In pro-inflammatory conditions, photobiomodulation can suppress NF-κB activation, leading to reduced production of pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6. Conversely, in immunosuppressed states, photobiomodulation may enhance NF-κB activity to boost immune responses [10].

Hamblin (2022) reported that photobiomodulation could reduce NF-κB activation by up to 30% in inflamed tissues, contributing to its anti-inflammatory effects in conditions like rheumatoid arthritis and inflammatory bowel disease [11].

MAPK pathway effects

The mitogen-activated protein kinase (MAPK) pathways, including ERK, JNK, and p38, are crucial in cellular responses to various stimuli, including stress and inflammation. Photobiomodulation has been found to modulate these pathways, influencing cell proliferation, differentiation, and cytokine production [12].

Photobiomodulation-induced activation of ERK has been associated with enhanced proliferation and survival of immune cells, while modulation of p38 MAPK has been linked to altered cytokine production profiles [13]. These effects contribute to the overall immunomodulatory impact of photobiomodulation, allowing for fine-tuning of immune responses based on the specific cellular context and treatment parameters.