Actinic Keratosis (AK)

Photodynamic therapy (PDT) has become an established first-line treatment for patients with multiple and confluent actinic keratoses (AKs). Its ability to achieve high clearance rates while maintaining excellent cosmetic outcomes has made it particularly valuable for lesions located on cosmetically sensitive areas such as the face and scalp. In addition to targeting visible lesions, PDT treats subclinical field cancerization, thereby reducing the risk of new lesion development and progression to invasive squamous cell carcinoma [16,17].

Randomized controlled trials have consistently demonstrated that PDT offers efficacy comparable to cryotherapy and topical chemotherapeutic agents such as 5-fluorouracil and imiquimod. However, unlike these destructive or pro-inflammatory alternatives, PDT has the added advantage of addressing wider areas of photodamage and field carcinogenesis in a single session. This broad-spectrum efficacy, combined with a superior cosmetic profile, has secured PDT a key role in dermatologic oncology [16].

A major advance in AK management has been the introduction of daylight PDT, which eliminates the need for conventional red-light illumination. Large-scale clinical trials confirm that daylight PDT provides similar efficacy while being almost pain-free and significantly more convenient for patients [18]. By improving tolerability and reducing treatment-associated discomfort, daylight PDT has expanded the accessibility and acceptance of PDT, further consolidating its role as a cornerstone therapy for actinic keratoses.

Bowen’s Disease (Squamous Cell Carcinoma in situ)

Bowen’s disease, or squamous cell carcinoma in situ, is highly responsive to photodynamic therapy (PDT), with clearance rates ranging from 70–90% after multiple treatment sessions [19]. PDT is especially advantageous for elderly patients or those with comorbidities who may not be ideal candidates for surgical excision. Its non-invasive nature, excellent cosmetic outcomes, and ability to treat multiple lesions in a single session make it a strong therapeutic option.

When compared to excision or cryotherapy, PDT provides significant benefits in large, multifocal, or anatomically challenging lesions, such as those on the lower legs, digits, or face, where tissue preservation and cosmesis are paramount [19]. This tissue-sparing approach helps avoid functional impairment and disfigurement, which are more likely after surgical procedures in sensitive areas.

Although recurrence rates with PDT tend to be somewhat higher than those reported for surgery, repeat treatments are feasible, safe, and well tolerated [20]. Long-term follow-up studies support its use as a valuable alternative or adjunct to surgery, particularly in patients where morbidity or cosmetic compromise is a concern. Thus, PDT continues to play an important role in the management of Bowen’s disease, striking a balance between efficacy, tolerability, and aesthetic outcomes.

Basal Cell Carcinoma (BCC)

Photodynamic therapy (PDT) is an approved and well-established treatment for superficial basal cell carcinoma (sBCC), with reported clearance rates of up to 80–90% in carefully selected lesions [21]. PDT is particularly valuable in patients with multiple lesions, in those who are unfit for or unwilling to undergo surgery, and in cosmetically sensitive sites such as the face, neck, or décolletage. In these scenarios, PDT offers a tissue-sparing approach with excellent cosmetic outcomes, while avoiding surgical morbidity and scarring.

For nodular basal cell carcinoma (nBCC), response rates are lower due to the limited depth of photosensitizer and light penetration [22]. However, recent studies suggest that efficacy can be improved with pretreatment modalities such as curettage, fractional ablative lasers, or microneedling, which enhance drug delivery into deeper tumor layers [23]. While surgery remains the gold standard for nodular and infiltrative BCC, PDT represents a valuable alternative or adjunct in selected cases, especially when preserving function and cosmesis is a priority.

Cosmetic Outcomes and Field Cancerization

A major advantage of PDT is its ability to simultaneously treat visible and subclinical lesions across a cancerized field. This reduces the likelihood of recurrence and provides superior cosmetic results compared to destructive modalities [24]. Patients often report improved skin texture, reduced pigmentation, and enhanced cosmetic satisfaction following PDT [25].

Acne Vulgaris

Photodynamic therapy (PDT) has emerged as a promising option for moderate-to-severe acne vulgaris, particularly in patients who do not respond to conventional antibiotics or for whom isotretinoin is contraindicated. The mechanism involves activation of endogenous and exogenous porphyrins with blue and red light, generating reactive oxygen species (ROS) that exert bactericidal effects against Cutibacterium acnes and induce sebaceous gland shrinkage [24]. These combined actions address both the microbial and sebaceous components of acne pathogenesis, making PDT a multifaceted therapy.

Advances in PDT protocols have improved both efficacy and tolerability. Short-contact 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) regimens, as well as daylight-PDT, reduce pain and downtime while maintaining good response rates [25]. In refractory nodulocystic acne, fractional laser-assisted PDT enhances photosensitizer penetration and improves clearance rates [26]. Adverse effects are typically mild and transient, including erythema, burning, and post-inflammatory hyperpigmentation; these can be mitigated by strict photoprotection and individualized parameter adjustments in patients with darker skin types. Overall, PDT is gaining recognition as an effective, safe, and cosmetically acceptable adjunct or alternative in the management of acne.

Rosacea

PDT has been investigated as a potential treatment for inflammatory rosacea, with small clinical studies reporting improvements in both papulopustular lesions and background erythema [27]. The proposed mechanisms include modulation of vascular responses, reduction of sebaceous gland activity, and anti-inflammatory effects through generation of reactive oxygen species. While not yet a standard therapy, PDT offers a non-systemic alternative for patients who fail to respond to topical or oral agents.

Clinical responses, however, remain variable, and treatment-related discomfort such as burning or transient worsening of erythema is common. Optimal outcomes require careful adjustment of fluence and incubation times, along with cooling techniques to minimize flares [28]. PDT can also serve as a complementary approach to vascular lasers such as pulsed dye laser (PDL), particularly in patients with persistent erythema or telangiectasia, highlighting its potential role in multimodal rosacea management.

Viral Warts (HPV)

Photodynamic therapy (PDT) has shown promise in the treatment of recalcitrant viral warts, particularly plantar and periungual lesions that are resistant to conventional modalities such as cryotherapy, salicylic acid, or keratolytic agents [29]. The mechanism is thought to involve selective uptake of the photosensitizer into HPV-infected keratinocytes, followed by light activation that induces cytotoxicity and antiviral immune responses.

Clinical experience suggests that pretreatment strategies such as keratolysis, curettage, or microneedling significantly improve outcomes by enhancing photosensitizer penetration through the thick hyperkeratotic stratum corneum [30]. This is especially important in plantar and periungual sites, where barrier effects of keratin often reduce the efficacy of topical treatments.

Although multiple PDT sessions are often required to achieve clearance, cosmetic results are excellent. Importantly, PDT spares the delicate periungual nail folds from the scarring or permanent damage that may follow aggressive surgical or ablative procedures [31]. Thus, PDT represents a valuable alternative for difficult warts, balancing efficacy, tolerability, and cosmetic outcomes in otherwise treatment-resistant disease.

Cutaneous Leishmaniasis

As an adjunct therapy in cases where systemic treatment is contraindicated, poorly tolerated, or unavailable, photodynamic therapy (PDT) has demonstrated the ability to reduce lesion burden and accelerate re-epithelialization [32]. Its non-invasive nature and favorable cosmetic outcomes make it an attractive option for patients with localized disease, particularly in resource-limited or endemic regions where access to systemic agents may be restricted.

The best clinical responses have been observed in localized, non-mucosal disease with thin plaques or ulcerative lesions of limited depth [33]. However, treatment protocols remain highly variable, with differences in photosensitizer selection (ALA vs MAL vs second-generation agents), incubation periods, and illumination parameters. For PDT to become more widely adopted in cutaneous leishmaniasis, there is a need for standardized protocols covering light dose, treatment intervals, and analgesic regimens, ensuring reproducibility and safety across centers.

Onychomycosis

Onychomycosis remains a therapeutic challenge, especially in patients who cannot receive systemic antifungals due to hepatic comorbidities, drug interactions, or personal preference. Photodynamic therapy (PDT) has emerged as a potential alternative or adjunctive therapy, leveraging the selective uptake of photosensitizers into fungal elements followed by photoactivation and generation of reactive oxygen species [34]. Its non-systemic nature offers a safer profile for vulnerable patient groups.

A key limitation of PDT in onychomycosis is the barrier effect of the nail plate, which restricts penetration of both photosensitizer and activating light. Strategies to overcome this include mechanical or chemical nail plate abrasion, as well as fractional laser-assisted channels that create microconduits to enhance delivery [35]. These approaches have been associated with improved treatment responses, though results remain variable across studies.

Clinical outcomes with PDT in onychomycosis are generally modest compared to its use in actinic keratosis or basal cell carcinoma. Multiple treatment sessions are usually required, and complete clearance rates are lower than those achieved with systemic terbinafine or itraconazole [36]. Nevertheless, PDT may still provide clinical benefit in carefully selected patients, particularly those seeking non-systemic options, or in combination regimens with topical antifungals.

In summary, while PDT is not yet a mainstream therapy for onychomycosis, it represents a viable adjunct for difficult-to-treat cases. Patient counseling is critical to set realistic expectations, highlighting the need for multiple sessions and the possibility of partial rather than complete clearance. Ongoing refinements in photosensitizer formulations and laser-assisted delivery may expand the utility of PDT for this stubborn infection in the future.

Antimicrobial/Antibiofilm Use

Antimicrobial photodynamic therapy (aPDT) has gained attention as a novel non-antibiotic approach for treating colonized chronic wounds, bacterial folliculitis, and infections caused by resistant organisms such as Staphylococcus aureus [37]. The mechanism relies on photosensitizer activation to generate reactive oxygen species, which damage microbial cell walls, DNA, and proteins, effectively disrupting bacterial viability and biofilms. This broad-spectrum, resistance-independent activity makes PDT particularly attractive in an era of escalating antimicrobial resistance.

Despite its potential, practical limitations remain. Photosensitizer preparation and incubation add to treatment time, while restricted light penetration poses challenges for deeper-seated infections [38]. Furthermore, repeated sessions are often required for durable clearance, which may limit patient adherence. Nevertheless, ongoing research into optimized photosensitizers, portable light devices, and biofilm-targeted protocols suggests that PDT could evolve into a valuable adjunctive tool for managing chronic, colonized, or drug-resistant infections in dermatology and wound care.

Practical Pearls

Established clinical applications of photodynamic therapy (PDT) in dermatology, including protocols, clearance rates, and outcomes, are summarized in Table 1 [28–37]. Beyond these established applications, PDT has also been studied in several emerging indications, summarized in Table 2 [39–53].

	Table 1: Established clinical applications of PDT in dermatology: treatment protocols and outcomes.
	Table 2: Emerging clinical applications of PDT: protocol tips and evidence level.

Daylight PDT

Daylight photodynamic therapy (DL-PDT) is increasingly recognized as a practical and tolerable alternative to conventional red-light PDT for actinic keratoses and field cancerization [38]. Randomized controlled trials confirm comparable efficacy for thin AKs, while reporting markedly reduced pain and improved patient satisfaction [39].

Beyond clinical efficacy, DL-PDT offers logistical advantages, including shorter preparation times and the elimination of specialized light sources. However, limitations remain: its effectiveness is climate-dependent and it demonstrates lower efficacy in thicker lesions, often necessitating adjunctive measures such as lesion debulking or combined therapies [40].

Fractional laser-assisted PDT

The use of fractional ablative lasers (CO₂ or Er:YAG) as a pretreatment strategy has been shown to significantly enhance photosensitizer penetration into deeper or hyperkeratotic tissue [41]. This approach facilitates more effective accumulation of ALA/MAL within diseased cells, thereby increasing treatment efficacy.

Clinical studies demonstrate that fractional laser-assisted PDT achieves improved clearance rates in thick actinic keratoses, nodular basal cell carcinoma, and recalcitrant viral warts compared with conventional PDT [42]. The technique is especially useful in cases where standard PDT penetration is insufficient, offering a non-surgical alternative for otherwise challenging lesions.

However, the method is not without drawbacks. Pretreatment with ablative lasers is associated with greater discomfort and downtime compared with conventional PDT. Despite this, fractional laser-assisted PDT remains a valuable option for difficult-to-treat lesions and for use in cosmetically sensitive areas where tissue preservation is critical [43].

Nano-formulated Photosensitizers

Nanoparticle-based photosensitizers, including liposomal ALA, polymeric nanoparticles, and chlorin derivatives, have been developed to improve cutaneous uptake, enhance stability, and increase lesion selectivity [44]. These advanced delivery systems aim to overcome limitations of conventional photosensitizers, particularly their poor penetration and rapid degradation.

Preclinical and early clinical studies suggest that nano-formulated PDT may achieve superior efficacy with potentially reduced systemic toxicity compared with traditional agents [45]. Such systems allow for more targeted delivery of active compounds, minimizing collateral tissue damage while enhancing phototoxic effects within diseased cells.

Although not yet widely available in dermatology practice, nano-formulated PDT represents a promising future direction, potentially expanding the clinical utility of PDT across a broader range of cutaneous diseases [46].

Combination Approaches with Immunotherapy and Biologics

Combining PDT with immunotherapies, checkpoint inhibitors, or biologics is an area of growing interest. PDT-induced immunogenic cell death may enhance systemic antitumor immune responses, providing a strong rationale for synergistic regimens [47].

Emerging clinical observations, including case reports, describe the use of PDT alongside biologics in inflammatory dermatoses such as psoriasis and hidradenitis suppurativa [48]. These preliminary findings raise the possibility that PDT could complement existing targeted therapies by modulating both immune and disease-specific pathways.

Nevertheless, robust evidence is still lacking. Controlled clinical trials are essential to determine the safety, efficacy, and long-term outcomes of such combined regimens, particularly regarding the risks of immune-related adverse events [49].

Recent advances in PDT delivery technologies, including laser-assisted PDT, daylight PDT, nanocarriers, and fractionated light protocols, are summarized in Table 3 [43–49].

Table 3: Advances in PDT delivery: mechanisms, advantages, and limitations.

Acute Side Effects

The most common adverse events during PDT are acute local skin reactions, including pain, erythema, edema, and crusting at the treatment site [50]. Pain – often described by patients as a burning or stinging sensations – tends to peak during illumination with red light and represents one of the major barriers to patient acceptance of PDT.

Although these acute reactions are generally self-limiting within a few days, they can impact adherence. In certain sensitive individuals, the severity of discomfort may even necessitate treatment interruption or discontinuation [51]. Consequently, strategies such as daylight PDT, cooling devices, and topical or systemic analgesia are increasingly incorporated into clinical protocols to improve tolerability.

Chronic and Delayed Adverse Effects

Chronic or delayed adverse effects after PDT are rare, but when present may include dyspigmentation, persistent erythema, and superficial scarring [52]. These complications are more likely to occur in patients with darker skin phototypes or in cases where high fluence settings or repeated PDT sessions are used.

Importantly, current evidence does not support an increased risk of photocarcinogenesis associated with PDT, even after multiple treatment cycles. This finding underscores its strong safety profile and supports the use of PDT as a long-term, field-directed therapy for chronic or recurrent dermatologic conditions [53].

Strategies to Improve Tolerability

Multiple strategies have been proposed to improve patient comfort during PDT. Cooling measures such as air cooling, cold water sprays, or the use of topical anesthetics and systemic analgesics can help reduce procedure-related pain [54].

Further optimization of treatment protocols-such as shorter incubation times and fractionated illumination schedules-has also been shown to enhance tolerability without significantly compromising efficacy [55].

Among recent innovations, daylight PDT represents a major advance, providing a near-painless treatment option with clearance rates comparable to conventional PDT for thin actinic keratoses. This approach has greatly expanded patient acceptance and practical use in dermatology [56].

The safety profile of PDT is well characterized, with acute side effects such as pain and erythema, and potential long-term sequelae such as dyspigmentation. Management strategies for these adverse events are summarized in Table 4 [50–56].

Table 4: Safety profile of PDT: acute and longterm side effects, and management strategies.

PDT versus Cryotherapy, Laser, and Topical Chemotherapy

Photodynamic therapy compares favorably with established destructive and topical treatments for actinic keratoses and superficial non-melanoma skin cancers. Compared to cryotherapy, PDT provides equivalent or superior clearance rates with significantly better cosmetic outcomes and reduced risks of hypopigmentation or scarring [57].

In contrast to ablative laser therapy, PDT is less invasive and allows for field-directed treatment of multiple lesions simultaneously, although lasers remain preferable for thicker or resistant tumors [58].

Topical chemotherapy agents, such as 5-fluorouracil (5-FU) and imiquimod, achieve high clearance rates but often require prolonged treatment courses with intense inflammation. PDT, by contrast, is typically completed in fewer sessions, thereby improving adherence and overall tolerability [59].

Cost-effectiveness

Economic analyses suggest that PDT is a cost-effective strategy, particularly when used for field cancerization and multiple lesions. While upfront costs may be higher than cryotherapy, reduced recurrence rates, fewer follow-up visits, and shorter recovery times support its overall economic advantage [60]. Daylight PDT further improves cost-effectiveness by reducing equipment and staffing requirements, making it attractive for large-scale use in primary care and dermatology settings.

Patient-reported Outcomes

Patient satisfaction is consistently higher with PDT than with destructive modalities. Cosmetic outcomes, particularly the absence of scarring and pigmentary changes, are rated superior to cryotherapy and surgery [57,60]. The shorter downtime and improved quality-of-life scores reinforce its role as a patient-preferred option for superficial premalignant and malignant lesions. These advantages have made PDT an increasingly favored therapy where long-term cosmetic and functional outcomes are priorities.

Pain as a Limiting Factor

Despite its many advantages, pain remains one of the most significant drawbacks of PDT, particularly during red-light illumination [61]. While strategies such as cooling, reduced incubation times, and daylight PDT have been developed to mitigate this issue, many patients still report discomfort severe enough to limit widespread adoption.

Limited Penetration in Thicker Lesions

The restricted penetration of photosensitizers and light reduces PDT efficacy in thicker actinic keratoses, nodular basal cell carcinoma, and deeply infiltrating lesions [62]. Adjunctive methods such as fractional laser-assisted PDT and microneedle delivery systems show promise in improving outcomes. However, their accessibility, cost, and need for specialized equipment remain barriers to routine clinical use [63].

Accessibility and Reimbursement Issues

In several healthcare systems, PDT is not universally reimbursed, which limits access for both patients and clinicians [64]. The high upfront costs of photosensitizers and illumination devices further restrict uptake, even though long-term evidence supports PDT’s cost-effectiveness in treating field cancerization.

Standardization of Protocols

Another major challenge is the lack of standardized protocols across different countries and clinical centers. Considerable variability exists in incubation times, choice of light sources (LED vs daylight), fluence levels, and lesion preparation methods [65]. This heterogeneity complicates the interpretation of clinical trials and hinders the development of universal treatment guidelines, slowing broader adoption.

Next-Generation Photosensitizers

Ongoing research is focused on developing novel photosensitizers with improved tumor selectivity, deeper tissue penetration, and reduced phototoxicity. Nanoformulated carriers and targeted delivery systems may further expand PDT applications to thicker and more aggressive skin tumors [66].

Artificial Intelligence for Treatment Planning

Artificial intelligence (AI) and machine learning are increasingly being explored to optimize PDT protocols by predicting lesion response, tailoring light dosimetry, and enhancing diagnostic accuracy through imaging integration. These approaches hold promise for protocol standardization across centers while reducing operator variability [67].

Role of PDT in Combination Cancer Therapy

There is growing interest in combining PDT with immunotherapies and biologics to exploit its immunomodulatory effects. Preclinical and early clinical studies indicate synergistic potential, particularly in enhancing anti-tumor immune responses and overcoming resistance to conventional therapies.

Personalized Medicine Approaches

The integration of genomic, proteomic, and imaging biomarkers may help identify patients most likely to benefit from PDT. Such personalized strategies could allow adjustment of photosensitizer type, incubation duration, and illumination parameters, thereby improving both efficacy and safety [68].

Key clinical and practical messages regarding the use of PDT in dermatology are summarized in Table 5.

Table 5: Key messages in photodynamic therapy.