The pioneering PSs, known as first-generation PSs, largely comprise hematoporphyrin derivative (HpD) and Photofrin. Hematoporphyrin was one of the first agents discovered to have photosensitizing properties and was later developed into HpD and Photofrin to enhance its effectiveness in PDT (3). HpD and Photofrin are complexes of various porphyrin derivatives. The primary characteristic of these PSs is the presence of porphyrin structures, which absorb light, particularly in the red region of the electromagnetic spectrum, and interact with molecular oxygen to generate ROS that induce cell death (22). Despite their effectiveness in causing photo-damage to cells, these first-generation PSs have limitations. They have a relatively weak absorption at therapeutic wavelengths (>600 nm), limiting the depth of tissue penetration. Moreover, these agents also have low tumor selectivity, leading to damage to healthy tissues. Prolonged skin phototoxicity is another drawback, with patients becoming sensitive to light for several weeks after treatment (23).

Due to the drawbacks of the first-generation PSs, more research was conducted on the second-generation PSs with strong ¹O₂ production and near-infrared (NIR) activation. Second-generation PSs include both porphyrinoid and non-porphyrinoid compounds ( Figure 1 ) (24). The former consists of macrocyclic structures like porphyrin, chlorins, bacteriochlorins, phthalocyanines, pheophorbides, bacteriopheophorbides, Porphycene, and texaphyrins, whereas the latter comprises anthraquinones, phenothiazines, xanthenes, cyanines, and curcuminoids (24). Metalated derivatives such as aluminum phthalocyanine tetrasulfonate (AlPcS4), Si (IV)-naphthalocyanine (SiNC), zinc phthalocyanine (ZnPC), and tin ethyl etiopurpurin (SnET2) are also included, although metalation doesn’t consistently enhance photodynamic activity (25). Second-generation PSs are superior to HpD in terms of ¹O₂ quantum yields, tumor-to-normal tissue concentrations, and antitumor effects (26). They also offer practical advantages like shorter tissue accumulation time, enabling same-day treatment and making PDT more convenient for out-patient procedures. Furthermore, these PSs exhibit a reduced window of cutaneous photosensitivity (27). Several factors, including lipophilicity, the type and number of charged groups, charge-to-mass ratio, and the type and number of ring and core substituents, influence the properties of the PSs (28). Most of the second-generation PSs, particularly those with porphyrin ring structures, are hydrophobic, affecting their administration, biodistribution, and pharmacokinetic profile (11). Although hydrophobicity enables cellular penetration, extreme hydrophobicity could cause aggregation in aqueous solution, compromising its pharmacokinetics and photophysical properties. Moreover, it could restrict solubility in physiological solvents and body fluids, thus limiting clinical applications. Hence, a balance between hydrophilicity and lipophilicity is critical for a clinically successful PS. This balance can be achieved by introducing hydrophilic polar substituents in the lead PS structure to synthesize amphiphilic derivatives. Other modifications, such as oxidation, extension, or modification of the porphyrin ring system to carry a central ion, can also enhance photophysical and pharmacological properties (29).

Present research primarily focuses on the development of third-generation PSs that are expected to enhance tumor specificity, minimize generalized photosensitivity, and be activated with longer-wavelength light (30). These improvements could be accomplished by modifying existing PSs with biological conjugates like peptides, antibodies, or antisense molecules for tumor-specific targeting, or by chemically conjugating or encapsulating PSs in efficient delivery vehicles or carriers (31–33). In essence, these third-generation PSs represent advancements over their second-generation counterparts in terms of improved delivery and targeting abilities. Specifically, they are designed to bind selectively to tumor cells or elements of the TME, consequently boosting tumor localization while reducing phototoxicity to healthy tissue.

Organic nanoparticles like micelles, liposomes, and dendrimers have been extensively investigated for PS delivery in PDT. Liposomes are spherical vesicles composed of phospholipid bilayers, which can encapsulate both hydrophilic and hydrophobic PSs (38). Micelles are self-assembled aggregates of amphiphilic molecules that can solubilize hydrophobic PSs within their hydrophobic core (39). Dendrimers are highly branched, tree-like polymers with a high degree of molecular uniformity and tunable surface functional groups, which can be used to conjugate PSs (39). Chen et al. developed a hybrid protein oxygen nanocarrier with chlorine e6 (Ce6) for oxygen self-sufficient PDT, which substantially decreased tumor hypoxia and improved the efficacy of PDT and the infiltration of CD8⁺ T cells at the cancer location (40). The increased PDT caused strong ICD and effectively inhibited primary tumors and suppressed pulmonary metastasis by stimulating more dendritic cells (DCs), NK cells, and cytotoxic T lymphocytes (CTLs) by increasing the release of damage-associated molecular patterns (DAMPs) ( Figure 2A ). A recent study improved the efficacy of PDT by using oxygen-laden hemoglobin (Hb) loaded auxiliary liposomes in conjunction with indocyanine green (ICG) modified gold nanospheres (41). Upon reaching the hypoxic tumor environment, the oxygen is rapidly released from the Hb, aiding the ICG in generating robust ROS and enhancing the immune response’s intensity ( Figure 2B ).

Inorganic nanoparticles, such as gold nanoparticles, silica nanoparticles, and quantum dots ( Figure 3 ), have also been investigated for PS delivery (45, 46). Gold nanoparticles (AuNCs) can be easily functionalized with various ligands and PSs, allowing for targeted delivery and controlled release (47). Silica nanoparticles are highly biocompatible and can be modified with various functional groups to improve PS loading and release (43). Quantum dots, semiconductor nanoparticles with size-tunable optical properties, can act as both PSs and imaging agents in PDT (44). Manganese dioxide (MnO₂) can stimulate the overproduction of hydrogen peroxide in tumor cells, resulting in the production of oxygen (48). Additionally, AuNCs act as intrinsic inorganic PSs that can induce ROS production, and the use of gold-based nanomedicines can enhance the effectiveness of other PSs in PDT due to the presence of a localized electric field (42, 49).

PSs can be conjugated with targeting ligands, such as antibodies, peptides, or small molecules, to enhance their tumor specificity and uptake (66, 67). Targeted delivery of PSs can be achieved using nanoparticles functionalized with specific ligands or antibodies that recognize receptors overexpressed on tumor cells or within the TME (68, 69). This strategy can improve the selectivity of PDT, reducing off-target toxicity and enhancing therapeutic efficacy. For example, folic acid-functionalized gold nanoparticles loaded with the PS chlorin e6 have demonstrated improved targeting and PDT efficacy in folate receptor-overexpressing cancer cells (70) A PS conjugated with an epidermal growth factor receptor (EGFR)-targeting peptide demonstrated improved PDT efficacy in EGFR-overexpressing cancer cells (71).

Due to the enhanced penetration and retention (EPR) effect that results from tumor vessel permeability, nanoparticles accumulate in tumor cells (72–74). Song et al. reported the development of PS-conjugated immune checkpoint inhibitor nanoparticles. As shown in Figure 5A , because of the EPR effect, these nanoparticles collect within tumors, Targeted delivery of PS and checkpoint inhibitor slowed tumor regrowth, prevented lung metastasis, and increased CD8⁺ T cells systemically (75). The hybrid nanoparticles that release PS and glucocorticoid-induced tumor necrosis factor receptor family-related protein, or poly (lactic-co-glycolic acid) (GITR-PLGA), utilize the immune activating role of PDT and GITR-PLGA-mediated suppression of immunosuppression to increase the amount of anti-tumor CD8⁺ T cells in the tumor (16).

Dual-function PSs have attracted considerable interest because of their multifunctional characteristics, that make them appropriate for imaging and treatment using PDT. This integrated method enables continuous tracking of the therapy process, enhancing the efficiency and precision of PDT (77). ICG is a well-known example of a dual-function PS. It is a water-soluble tricarbocyanine dye with widespread use in medical diagnostics for its fluorescence imaging capabilities (78). In recent years, researchers have also discovered its potential for PDT applications. ICG has shown efficacy in both in vitro and in vivo experiments, showing its potential for imaging and treating malignant tumors simultaneously (79). Porphysomes, another example of dual-function PSs, are self-assembled porphyrin-lipid nanoparticles. These unique structures exhibit excellent photoacoustic imaging and PDT properties. Porphysomes have been shown to generate a strong photoacoustic signal in response to laser irradiation, allowing for high-resolution imaging of targeted tissues. Moreover, porphysomes can generate cytotoxic ROS upon light activation, leading to targeted destruction of cancer cells (80).

The restricted absorption of light into tissues limits treatment to surface tumors or requires invasive procedures for deeper tumors (27, 81). To overcome this limitation, researchers have explored strategies such as the use of upconversion nanoparticles (UCNPs), which convert NIR light to higher-energy light that is visible, allowing deeper tissue penetration without damaging surrounding tissues (82, 83).

UCNPs are nanoscale materials that convert low-energy light to high-energy light by sequentially exciting multiple photons via an anti-Stokes emission process. Compared with downconverted nanoparticles, UCNs can absorb NIR light and have a relatively high depth of tissue penetration, while the light can be converted into strong ultraviolet or visible light, enabling the activation of PSs in deep tissues (84). When coupled with PSs, UCNPs can extend the tissue penetration depth of PDT, improving its efficacy in the treatment of deep-seated tumors (85–89).

UCN-based PDTs have been extensively studied for tumor therapy due to their ability to improve tissue penetration depth. A study by Ai et al. utilized this feature by constructing Ce6-loaded UCNs combined with HA and MnO₂ nanosheets to enhance NIR light-mediated PDT ( Figure 5B ). By converting 808 nm light excitation into 655 nm emissions, the Ce6-loaded UCNs efficiently generated sufficient ¹O₂ to induce deep-tissue cellular ablation. Additionally, the surface-anchored HA inhibited tumor recurrence post-PDT treatment by producing M1-type macrophages instead of M2-type macrophages (76).

PDT has been demonstrated to elicit ICD, increasing immune responses, which stimulates the immune system against dying cancer cells (90, 91). When combined with Adoptive T cell therapy, Cancer vaccine, and Immune checkpoint inhibitor, the ideal mechanism is currently speculated as Figure 6 (92–94). ICD promotes the release of DAMPs and TAAs, which act as danger signals to activate antigen-presenting cells (APCs) and initiate an immune response (95). PDT can activate APCs, such as DCs, through the release of DAMPs and the upregulation of costimulatory molecules. When immature DCs migrate from peripheral organs to neighboring draining lymph nodes, they gather antigens from the surrounding fluid, convert them into peptides, and then present the peptide major histocompatibility complex (MHC) at T cell receptors (TCR) triggering T cell activation, thereby priming and activating tumor-specific CTLs (96, 97). PDT has been reported to enhance the infiltration of T cells into the TME by modulating the expression of chemokines and adhesion molecules, thereby promoting the attraction of CTLs along with additional immune cells to the tumor location (98).

Several preclinical studies have demonstrated the potential of combining PDT with immunotherapy, resulting in improved antitumor effects and long-lasting immune responses (36, 101). In a mouse model of melanoma, the combination of PDT and anti-PD-1 therapy led to enhanced tumor regression and improved survival rates (99, 115, 116). Another study showed that combining PDT with a cancer vaccine increased antitumor immunity and prevented tumor recurrence in a mouse model of colon cancer (117). Bao et al. targeted IRDye700 to subcutaneous murine 4T1 tumors using a Fab portion of an antibody that attaches to CD276, an antigen specifically expressed on tumor cells. While targeted NIR therapy reduced tumor regeneration, PD-L1 expression on tumor cells increased significantly. By combining CD276-targeted NIR-PIT and anti-PD-L1 therapy, they were able to prevent subcutaneous tumor regrowth and lung metastasis (69). Hao et al. developed a combined therapy approach using PDT and immune checkpoint blockade to optimize tumor control. They incorporated a 25% thermosensitive polymer 407 hydrogel as a co-delivery platform for this treatment strategy. NIR PDT at 808 nm irradiation, along with CTLA4 and PD-L1 checkpoint blockade, suppressed solid tumor growth and extended the survival rate of colorectal tumor-bearing mice. This was achieved by eliciting a range of immune responses, including macrophage and DCs phagocytosis of tumor debris, acute inflammation induction, leukocyte infiltration, as well as maturation and activation of DCs (20). In the study by Santos and colleagues, the use of PDT with redaporfin successfully eradicated all observable tumor tissue. Subsequently, the application of an immune checkpoint inhibitor contributed to a sustained complete response in the clinical setting. This particular case exemplifies the potential effectiveness of such a combined therapeutic approach, laying the foundation for the development of a novel treatment strategy (118).

Potential side effects of PDT, including skin photosensitivity, pain, and edema, stem from prolonged presence and systemic distribution of PSs (119). Addressing these concerns, nanotechnology provides targeted PS delivery, reducing off-target phototoxicity. Biodegradable CaCO3/MnO2-based nanocarriers have been successfully used to transport PSs, demonstrating significant advancements over potentially toxic gold-based nanomedicines (120). These nanoparticles, engineered to accumulate in tumors through the enhanced EPR effect, limit PS exposure in healthy tissues (103). Surface modifications with tumor-specific ligands further enhance nanoparticle specificity, minimizing non-target skin photosensitivity (4, 104). Some nanoparticles also provide controlled PS release in response to stimuli such as pH, temperature, or enzymes, localizing PS activation to the treatment area (121).

An emerging trend in cancer treatment is the development of personalized medicine, which tailors treatments to the distinctive features of a patient’s tumor (122, 123). The combination of PDT and immunotherapy allows for a more tailored approach by considering factors such as TME, immune profile, and response to treatment (94, 124). Identifying predictive biomarkers and developing treatment algorithms based on individual patient profiles will be crucial for improving patient outcomes (124).

Translating preclinical research findings into clinical practice remains a challenge for the field. Issues such as regulatory approval, manufacturing, and standardization of treatment protocols need to be addressed to ensure the successful clinical translation of nanotechnology-enabled PDT and immunotherapy (18, 125). Collaborative efforts between researchers, clinicians, and regulatory agencies are necessary to accelerate the development and approval of these innovative therapies (126, 127).

In conclusion, the exciting interplay of nanotechnology-enabled PDT, advanced PSs, and immunotherapy heralds a promising new era in cancer treatment. The potential to overcome limitations such as tissue penetration and side effects, coupled with the opportunity to develop personalized cancer treatment strategies, paves the way for successful clinical translation. At the heart of this revolutionary approach lies the convergence of several disciplines. Material science, molecular biology, and biomedical engineering come together to optimize nanomaterials for improved delivery and activation of PSs, enhancing biocompatibility and maximizing therapeutic payloads. Moreover, an in-depth understanding of the TME is vital to design nanoparticles capable of navigating and penetrating these complex terrains effectively. Simultaneously, insights from the intersection of immunology and oncology spotlight the potential of leveraging PDT to stimulate potent immune responses against tumors. This accentuates the exciting prospects of integrating PDT and immunotherapy for comprehensive cancer treatment. Furthermore, the introduction of machine learning and computational modeling can advance nanotherapeutic design by predicting biological interactions, leading to more effective and targeted therapies. The translation of these advancements from lab to clinic necessitates meticulous testing and a thorough understanding of regulatory pathways. This underlines the significance of collaborative efforts between researchers, clinicians, and regulatory agencies. Ultimately, the future of PDT and nanotechnology, through this multi-disciplinary collaboration, holds immense potential in revolutionizing cancer therapy, improving patient outcomes, and providing benefits to cancer patients worldwide.