Cancer remains a global threat to human health due to its complex biological characteristics and effects in increasing morbidity and mortality (1). Although remarkable progress has been made in surgical techniques, chemotherapy, radiation therapy, and immunotherapy, which have significantly extended the survival times of cancer patients, there remains an urgent need for treatments that are both safer and more effective (2). Photodynamic therapy (PDT) has garnered significant attention as a promising cancer treatment (3), as it offers localized effects with minimal damage to surrounding healthy tissue, achieved using photosensitizers that generate reactive oxygen species (ROS) able to induce cell death under specific light wavelengths (4). PDT involves synergistic effects of photochemistry and photobiology, and offers an alternative to traditional cancer treatments (5).

PDT has transitioned from experimental studies to active clinical investigation, with over 60 registered clinical trials ( Supplementary Table S1 ) currently evaluating its efficacy across various cancer types in the last decade (6–8). Compared with conventional cancer treatments, PDT offers several distinct advantages. PDT employs noninvasive or minimally invasive techniques that effectively minimize collateral damage to healthy tissues. Moreover, PDT is associated with mild side effects, and can be repeatedly administered based on the patient’s clinical condition. Notably, PDT can be synergistically combined with other cancer treatment methods to enhance overall therapeutic efficacy while preserving the inherent benefits of the adjunct treatments. With ongoing advances in treatment protocols and innovative photosensitizer delivery technologies, PDT as a minimally invasive and precisely targeted treatment approach—holds significant potential to advance cancer therapy, improve patients’ quality of life, and increase the likelihood of recovery.

The therapeutic potential of PDT has been explored in various cancers, including skin, lung, esophageal, and head and neck tumors (9). The multiple mechanisms underlying PDT, including direct tumor cell killing, disruption of tumor blood vessels, and activation of immune responses, underscore its versatility (10). Despite promising results in many studies, the clinical application of PDT has been inconsistent, possibly due to variability in treatment regimens and differences attributable to cancer types and stages (8). Therefore, there is a pressing need to synthesize the existing research evidence to comprehensively evaluate the overall efficacy, safety, and clinical applicability of PDT across different cancer types.

Umbrella reviews of systematic reviews and meta-analyses can address this need by providing a high-level overview of current evidence, through integration and critical analysis of existing research data (11). In this study, we systematically evaluated the evidence from previous systematic reviews and meta - analyses to review the application of PDT in cancer treatment. Through this thorough analysis, our aim was to clarify the potential of PDT in cancer treatment and to lay a solid foundation for future research and clinical practice.

This study was conducted in accordance with the PRISMA guidelines (12) and its protocol was registered with PROSPERO (registration number: CRD42024538243).

The aim of this review was to investigate the evidence for associations between PDT and its efficacy and AEs in cancer treatment. We integrated data from 18 publications covering 8 types of cancer, involving 124 associations from paired meta-analyses and 34 associations from single-arm meta-analyses.

Cholangiocarcinoma is a rare, aggressive cancer originating from the bile ducts, for which PDT has emerged as a promising palliative treatment option (40). Due to the anatomical location and frequent late diagnosis of cholangiocarcinoma, treatment is challenging (41). Biliary stenting is commonly used for conservative treatment of unresectable cholangiocarcinoma, and addition of PDT may improve survival rates by reducing stent occlusion. Relative to biliary stenting alone, combined PDT significantly improves OS and reduces mortality by approximately 37% (RR 0.63, 95% CI 0.48–0.83), without increasing the risk of AEs; however, when only RCT studies were considered, the improvement in OS with PDT was not significant, suggesting potential reporting or publication bias. For hilar cholangiocarcinoma, re-synthesized meta-analysis showed that PDT combined with biliary stenting does not improve OS, indicating that previous effects may have been overestimated. This finding suggests that cancer type may influence PDT efficacy; the differences could be due to the anatomical complexity and aggressiveness of hilar cholangiocarcinoma, which pose significant challenges for effective PDT delivery and tumor eradication. Overall, these results indicate that, while PDT holds great potential for use against certain cholangiocarcinoma subtypes, its efficacy may be limited for others.

Previous meta-analyses have provided extensive evidence of the efficacy of PDT for non-melanoma skin cancers, particularly BCC and SCC. While surgical excision remains the gold standard for many melanoma skin cancers, particularly high-risk or aggressive lesions, PDT offers a non-invasive alternative that preserves tissue integrity and function, which is especially important for lesions on the face, ears, and other visible areas (42). Multiple guidelines recommend considering PDT for superficial or nodular BCC with small diameter (< 2 cm) and thin lesions (< 2 mm) in patients unsuitable for surgery (43–45). PDT has excellent cosmetic outcomes in patients with BCC, but lower complete response rates and higher recurrence rates than surgery and imiquimod. PDT also carries a higher risk of pain (15%–70%) and AEs than placebo, fluorouracil, and imiquimod, and a 64% higher risk of AEs than surgery; however, after accounting for publication bias using the trim-and-fill method, the risk of AEs associated with PDT relative to various other therapies lost significance, suggesting the presence of publication bias and potential biases due to heterogeneous comparisons.

Our quantitative analysis substantiates the cosmetic advantages of PDT, particularly in head-to-head comparisons with conventional therapies. The pooled data demonstrated that MAL-PDT achieved 3.46-fold better cosmetic outcomes than cryotherapy in SCC (RR 3.46, 95% CI 1.55-7.73), and maintained 2.90- to 3.99-fold superiority over both cryotherapy (RR 2.90) and surgery (RR 3.99) in BCC management. This magnitude of effects likely stems from PDT’s tissue-sparing mechanism: selective photosensitizer activation minimizes collagen disruption and preserves dermal architecture (46), whereas surgical excision inherently causes structural defects and cryotherapy induces collagen hyalinization (47). Notably, the absence of cosmetic difference between MAL-PDT and 5-fluorouracil suggests that non-invasive pharmacological approaches may share similar aesthetic preservation profiles. However, long-term cosmetic outcomes beyond 5 years remain unquantified, particularly regarding pigmentary changes. The trade-off between recurrence risk (RR 1.82 vs surgery) and cosmetic superiority necessitates shared decision-making, especially for high-risk tumors where oncologic control takes precedence.

PDT is generally well-tolerated, with side effects typically less severe than those from traditional treatments, such as surgery or radiation therapy (48). Common side effects include local skin reactions, such as erythema, edema, and pain at the treatment site, are usually mild to moderate, and generally resolve within days to weeks after treatment. Photosensitivity is a significant concern, necessitating strict light protection measures, to avoid adverse reactions (49).

In SCC populations, current evidence indicates that PDT results in comparable recurrence and complete response rates to cryotherapy and fluorouracil, but offers superior cosmetic outcomes relative to cryotherapy. Additionally, there is evidence that laser-assisted PDT is superior to conventional PDT in achieving complete response and reducing recurrence, without increasing the risk of AEs; however, after correcting for publication bias, the complete response rate of laser-assisted PDT does not differ significantly from that of conventional PDT. Furthermore, our analysis systematically compares the efficacy and safety profiles of distinct photosensitizers. Current evidence demonstrates no significant differences among ALA, MAL, and hexaminolevulinic acid in clinical outcomes. Notably, laser-assisted PDT using YAG-AFL-PDT shows potential superiority over MAL-PDT in both therapeutic response and recurrence reduction, while maintaining equivalent cosmetic outcomes and adverse event risks. This suggests that technological refinements in PDT delivery systems – rather than photosensitizer selection alone – may enhance therapeutic performance. Emerging clinical trials (ClinicalTrials.gov identifiers: NCT05374915, NCT02840331, NCT02367547, NCT06262555) are actively evaluating combinatorial PDT approaches with novel light sources and photosensitizer formulations. Future validation through network meta-analyses will be essential to delineate hierarchical efficacy patterns across PDT modalities once more comprehensive datasets from these studies become available.

Single-arm meta-analyses suggest that the relative efficacy of PDT varies across different cancers. For example, PDT demonstrates high efficacy and low recurrence rates in patients with cutaneous metastatic SCC and oral SCC, whereas it is less effective in primary cutaneous SCC and hilar cholangiocarcinoma. This variation may be influenced by the depth, organ, and nature of lesions. In addition, PDT has shown considerable therapeutic promise in prostate and bladder cancer, but higher levels of clinical evidence are needed (50, 51).

The three key elements influencing PDT efficacy are the photosensitizer, exposure to specific wavelengths of light, and oxygen (52, 53). Photosensitizers can be administered via intravenous injection or topical application, after which they accumulate in tumor tissue, due to characteristics such as leaky vasculature and an acidic environment, resulting in higher concentrations in tumor than in normal tissue (54). This selective accumulation helps minimize toxicity to normal tissue and enhances cancer specificity (55).

Under the influence of the photosensitizer, energy from light is transferred to molecular oxygen, producing reactive oxygen (ROS) including singlet oxygen (¹O₂₎, superoxide radicals (O2−•), hydroxyl radicals (HO•), and hydrogen peroxide (H₂O₂) (56, 57). PDT efficacy primarily relies on the generation of ¹O₂ (58), unlike molecular oxygen, which plays a passive role in cellular metabolism, has a short lifespan and exerts direct cytotoxic effects by damaging cellular components, including lipids, proteins, and DNA (59). The amount of ¹O₂ produced is a crucial determinant of PDT efficacy and is influenced by the type of photosensitizer, its subcellular localization, oxygen availability, and light fluence (60) ( Figure 5 ). Notably, recent research on porphyrin β - thiolation shows that progressive thiolation can switch ¹O₂ photosensitization, adding a new dimension to understanding the factors affecting ¹O₂ production in PDT (61).

Several strategies have been developed to enhance PDT efficacy by boosting ¹O₂ generation and improving light penetration. Metallic nanoparticles, such as gold and titanium dioxide, can amplify ROS production via plasmon resonance and electron transfer (62, 63). To address tumor hypoxia, oxygen-delivering nanocarriers like perfluorocarbons have been introduced to sustain ¹O₂ output (64). Meanwhile, near-infrared light sources (700–800 nm) enable deeper tissue penetration and improved therapeutic outcomes (65, 66). In addition, rational metal selection within photosensitizer complexes has emerged as an effective approach to modulate excited-state energy dissipation, thereby enhancing both photodynamic and photothermal therapeutic performance (67).

The pharmacokinetics of photosensitizers significantly impact PDT efficacy and safety (68). Most photosensitizers undergo hepatic metabolism and are eliminated via biliary or renal excretion (69, 70). Prolonged retention in healthy tissues, particularly the skin, may lead to photosensitivity-related toxicities (71). The development of tumor-targeting photosensitizers, such as those conjugated with antibodies, peptides, or folic acid, aims to improve tumor selectivity and minimize off-target effects (72–74). Enhanced permeability and retention effects in tumors facilitate the accumulation of macromolecular photosensitizers, further improving PDT specificity (75). Recently, bioinspired β-pyrrolic ring-opening seco-chlorins such as ZnBPL have been developed, which not only exhibit strong ROS generation and therapeutic efficacy but also undergo rapid metabolism, thereby reducing phototoxic side effects, representing a novel approach to enhance both the efficacy and safety of PDT (76).

Despite its selective tumor targeting, PDT is associated with various toxicities primarily related to photosensitizers. ROS can damage normal tissues, stimulate local immune responses, release inflammatory factors, induce oxidative stress, and trigger the release of cytokines, such as tumor necrosis factor-alpha, nitric oxide, histamine, and prostaglandin E2 (71), resulting in local inflammation and nerve ending stimulation. these inflammatory reactions also function in tissue repair, debris clearance, and internal balance restoration (77). Common adverse effects include local erythema, edema, and pain at the treatment site, which usually resolve within days to weeks (48). Strategies to mitigate these toxicities include dose optimization, light dose fractionation, and the development of rapidly clearing photosensitizers with improved photophysical properties (78, 79).

Factors affecting PDT efficacy include photosensitizer type, its specific localization in tumor tissue, light penetration depth, and local oxygen content (80). Porphyrin-based photosensitizers, which have a tetrapyrrole structure, are commonly used in cancer treatment, and should ideally have absorption peaks in the range 600–800 nm; light absorption and penetration are poor below 600 nm, while above 800 nm, light cannot excite oxygen molecules to singlet oxygen (81). Increasing wavelength enhances light penetration into tissues. Light source parameters and characteristics, including coherence, wavelength, and beam size, also influence PDT efficacy (82). The findings of our research indicate that laser light (a coherent light source) was slightly more effective in treating skin cancer than non-coherent light sources, and did not increase AEs. This may be because coherent light is monochromatic and can match the absorption peak of the photosensitizer, providing stronger penetration ability (83).

Combined PDT with chemotherapy, radiotherapy, or surgery demonstrates enhanced antitumor efficacy through synergistic mechanisms without increasing adverse events. For instance, doxorubicin-PDT combinations halve chemotherapy doses yet enhance cytotoxicity in breast cancer cells by overcoming multidrug resistance (84). This principle of localized oxidative damage amplification parallels recent advances in antibacterial chemodynamic therapy, where Fenton reaction-generated hydroxyl radicals synergize with photodynamic approaches to overcome biofilm resistance through microenvironment-specific ROS generation (85). Recent advances in photoimmunotherapy (PIT) further enhance therapeutic precision by leveraging antibody-targeted phototoxicity (Cetuximab-IR700 conjugates) and systemic immune activation, as evidenced by NK cell-mediated indocyanine green (ICG) delivery systems that synergize photothermal ablation with perforin/granzyme-dependent cytotoxicity (86, 87). Nanoparticle-mediated co-delivery of photosensitizers and chemotherapeutics (e.g., chlorin e6 with artesunate) leverages tumor-selective accumulation and controlled ROS-triggered drug release, improving therapeutic indices (88). This parallels PIT strategies utilizing nanocarriers (ICG-liposomes) to stabilize photosensitizers while exploiting immune cells (NK-92MI) as tumor-targeting vehicles, as demonstrated in dual-mechanism platforms (86, 87). Preclinical studies highlight pH- or enzyme-sensitive linkers in prodrugs, enabling localized activation and reduced systemic toxicity (89). Clinically, endoscopic PDT combined with gemcitabine/oxaliplatin for unresectable cholangiocarcinoma extends median survival by 1.5-fold versus monotherapies, with no added toxicity (40). PDT also radiosensitizes tumors: sequential PDT and radiotherapy for esophageal or lung cancer yield higher complete response rates via non-overlapping mechanisms (e.g., ROS-induced hypoxia enhancement) (90). Emerging strategies include PARP inhibitors (olaparib) with PDT, which lower light doses (25 vs. 100 J/cm²) while maintaining efficacy in gastric cancer models (91). These combinations exploit PDT’s spatial precision and immune modulation to amplify conventional therapies, underscoring their translational potential. Thus, rational pairing of PDT with chemotherapy, nanotechnology, or targeted agents offers a paradigm for improving survival without compromising safety. Notably, copper sulfide-based nanoplatforms exemplify this synergy by integrating photothermal ablation with chemotherapy and dynamic therapies, while enabling multimodal imaging-guided treatment to optimize tumor microenvironment modulation and minimize systemic toxicity (92).

To our knowledge, this is the first umbrella review to assess associations of PDT with cancer treatment, with a focus on evaluating methodological quality and evidence grades of relevant publications. We employed the CCA method to prevent duplication across studies and conducted a comprehensive meta-analysis to assess the current landscape. Additionally, we conducted a reanalysis using a random-effects model to identify and address publication bias, thereby strengthening the reliability of our results.

Nevertheless, our umbrella review has several important limitations that warrant consideration. First, most of the included studies were rated as having low or very low methodological quality. This was primarily due to inadequate reporting practices—including the lack of comprehensive literature lists, absence of pre-registration for study protocols, and insufficient assessment of bias risks—which collectively diminish the confidence in the reported findings. To address potential publication bias arising from these shortcomings, we conducted Egger’s test and generated funnel plot visualizations. Second, although subgroup analyses can provide insights into heterogeneity, our ability to perform such analyses based on key variables such as PDT dose, treatment duration, and ethnicity was constrained by the limitations inherent in the source meta-analyses. Where possible, we focused our subgroup analyses on the specific photosensitizers used and the treatment modalities applied in the control groups. However, this approach may not fully capture the influence of other clinically relevant factors. Third, the overall modest sample size across the studies contributes to the relatively low evidence grade (Class IV, weak evidence) observed in our review. This suggests that the results need to be interpreted with caution, in conjunction with other high-quality evidence or expert consensus. This limitation highlights the urgent need for larger, rigorously designed clinical trials—particularly randomized controlled trials—to further validate and expand upon our findings. Future studies should focus on optimizing PDT protocols, exploring new photosensitizers, and improving light delivery technologies, to enhance efficacy. Combination regimens require systematic investigation, including synergies with immune checkpoint inhibitors, hypoxia-activated prodrugs, and nanoparticle-mediated co-delivery systems to enhance therapeutic specificity. Multicenter consortia should establish standardized endpoints encompassing complete response rates, immune microenvironment modulation, and long-term recurrence metrics, while parallel cost-effectiveness analyses will be crucial for clinical translation. Personalized treatment approaches, based on genetic and molecular profiles, may also facilitate identification of patients most likely to benefit from PDT (68, 93) and prioritize robust methodological standards and comprehensive reporting to enhance the reliability of the evidence base for PDT in cancer treatment.

Current evidence indicates that PDT combined with stenting and chemotherapy in the treatment of cholangiocarcinoma decreases overall mortality and enhances OS. For patients with BCC and SCC, PDT results in higher recurrence rates than surgery, cryotherapy, and imiquimod, yet it yields superior cosmetic outcomes. Moreover, laser-based PDT demonstrates superior efficacy compared with conventional PDT. Overall, PDT shows promise for the treatment of prostate, oral, and bladder cancers.

PDT represents a versatile and evolving modality in cancer therapy, offering selective tumor targeting, cosmetic advantages, and potential synergy with novel technologies. However, efficacy varies across cancer types and is influenced by complex interactions among photosensitizers, light parameters, and tumor biology. Standardization of treatment protocols, development of next-generation photosensitizers, and high-quality RCTs across diverse indications are essential to establish PDT as a mainstream oncologic intervention.