Search Results (12,022)

Curcumin and natural curcuminoids possess numerous beneficial properties, including antioxidant, antitumor, and anti-inflammatory effects. However, their application is challenging because of instability and rapid metabolism. Cyclic C₅-curcuminoids, a subgroup of curcuminoids, are chemically more stable and less susceptible to hydrolysis or metabolism. In our study, seven synthetic compounds—five cyclic C₅-curcuminoids (compounds 8, 9, 11, 12, and 13) and two cyclic chalcones (compounds 4 and 5)—were examined using an in vitro 6-hydroxydopamine-induced neuronal damage model established with all-trans retinoic acid-differentiated SH-SY5Y and BV-2 microglial cells. The antioxidant, anti-apoptotic (including ferroptosis markers (iron, GSH/GSSG, and malondialdehyde)), apoptotic (PARP, cytochrome c, caspase 9, active caspase-3, and oligonucleosome release), and anti-inflammatory effects of these compounds were also investigated. Compounds 5, 9, 12, and 13 significantly decreased reactive oxygen species production (percentage changes: 5: 28.9%; 9: 32%; 12: 29.8%; 13: 49.2%) and increased antioxidant capacity (percentage changes: 5: 63.4%; 9: 85.8%; 12: 31.2%; 13: 85.9%) and antioxidant enzyme activity (catalase, superoxide dismutase, and glutathione peroxidase) in SH-SY5Y cells. Compounds 5, 9, and 12 decreased microglial activation by downregulating Iba1 expression (fold changes: 5: 0.73; 9: 0.39; 12: 0.33) and decreasing glutamate concentration (percentage changes: 5: 26.5%; 9: 41.2%; 12: 27.3%). Together with compound 13, they reduced pro-inflammatory cytokine (IL-6, TNFα) secretion and induced anti-inflammatory cytokine (IL-10) release in SH-SY5Y and BV-2 cells. Based on these results, the blood–brain barrier penetrations of compounds 5, 9, 12, and 13 were also investigated. The highest blood–brain barrier penetration was observed for compound 12 (P_app value 13.6 × 10⁻⁶ cm/s). Synthetic cyclic C₅-curcuminoids derived from curcumin overcome the limitations of stability and bioavailability and exhibit strong antioxidant, anti-inflammatory, and anti-apoptotic effects, making them promising candidates for treating neurodegenerative diseases. Full article

The aim of this study was to summarize current evidence on dust-related diseases of the bronchopulmonary system, medicinal plants, herbal formulations, and their underlying mechanisms of action. A literature review was conducted based on publications indexed in ScienceDirect, Google Scholar, SciFinder, Scopus, and Medline (PubMed), focusing on the mechanisms underlying dust-related diseases of the bronchopulmonary system, pneumoconiosis, and the potential of phytotherapeutic approaches to modulate these processes. The following keywords were used: bronchopulmonary system, pneumoconiosis, dust-related lung diseases, medicinal plants, herbal preparations, pulmonary rehabilitation, and lymphatic sanitation. The pathogenesis of pneumoconiosis involves the deposition of inhaled dust particles in the lung tissue, followed by chronic inflammation, oxidative stress, and progressive fibrosis. In experimental models, flavonoids, alkaloids, terpenoids, glycosides, tannins, and other phytochemical groups have demonstrated therapeutic potential in bronchopulmonary diseases. Among the compounds investigated, emodin, celastrol, kaempferol, sodium tanshinone IIA sulfonate, astragaloside IV, and dioscin have shown promising effects by modulating key signaling pathways and reducing inflammatory responses. Experimental evidence indicates that these phytochemicals can target major pathways involved in inflammation and fibrogenesis, thereby exerting antioxidant, anti-inflammatory, and antifibrotic effects. The lymphatic system also contributes to the pathogenesis of pneumoconiosis by transporting inhaled dust particles to regional lymph nodes, where their accumulation may promote lymph node sclerosis. Therefore, lymphatic sanitation may represent an important therapeutic mechanism of action of herbal formulations in pneumoconiosis. Our proposed lymphotropic herbal formulation enhances physiological lymphatic drainage and may positively influence the motility and functional activity of the tracheobronchial lymph nodes. The therapeutic potential of medicinal plants and herbal formulations in pneumoconiosis is supported by experimental findings for Tripterygium wilfordii (celastrol, through suppression of the EDNRB/Kng1 – (endothelin receptor type B/kininogen1), Delphinium, Camellia, and Berberis species (kaempferol, through inhibition of TLR4 (Toll-like receptor 4 signaling), Astragalus membranaceus (astragaloside IV, through antifibrotic activity mediated by inhibition of the TGF-β1/Smad3 (transforming growth factor beta1)pathway), and Reynoutria japonica Houtt., Rheum, and Aloe species (emodin, through inhibition of Smad3 (Smad family member 3) and NF-κB (nuclear factor kappa B)phosphorylation and reduction of TGF-β1, α-SMA (alpha-smooth muscle actin), collagen I, TNF-α (tumor necrosis factor alpha), and IL-1β (interleukin-1 beta) levels in lung tissue). For these and several other medicinal plants and their flavonoids, antifibrotic activity has been demonstrated through inhibition of the Akt/NF-κB (protein kinase B/nuclear factor kappa B) signaling pathway. A promising direction for future research is to evaluate the combined use of herbal formulations with established antifibrotic agents to determine whether synergistic therapeutic effects can be achieved. Full article

Interleukin-12 (IL-12) potently promotes the recruitment and activation of immune cells within the tumor microenvironment (TME), highlighting its immense potential for cancer therapy. However, its dose-limiting systemic toxicity and short half-life severely hinder its clinical translation. Here, we design a tumor-conditionally activated IL-12 prodrug termed αHSA-proIL-12. This engineered molecule integrates a cleavable albumin-binding nanobody (αHSA) domain to extend the half-life and enhance tumor targeting alongside a masking domain that occludes the IL-12 receptor-binding site to prevent nonspecific activation. This construct undergoes selective cleavage by matrix metalloproteinases (MMPs) that are highly expressed in the TME to release highly penetrant, free, low-molecular-weight IL-12 locally. This tumor-restricted activation process directly facilitates the selective recruitment and activation of tumor-infiltrating lymphocytes (TILs). The intravenous administration of an extremely low dose of 108 pmol per dose of αHSA-proIL-12 completely cleared MC38 tumors without inducing systemic toxicity. The maximum tolerated dose of this molecule exceeded 2 nmol, yielding a remarkably wide therapeutic index >18.5. Mechanistically, αHSA-proIL-12 effectively reprogrammed the immunosuppressive TME by expanding the numbers of effector CD8⁺ T cells and natural killer cells while upregulating IFN-γ expression and significantly reducing the proportion of regulatory T cells. This immunological remodeling has the potential to convert “cold” tumors into “hot” tumors. Notably, this treatment achieved complete regression and durable immunity in a subset of mice with multiple refractory immune-cold tumors, including Panc02 pancreatic cancer, 4T1 triple-negative breast cancer, and B16F10 melanoma, when administered as a monotherapy or in combination with PD-L1 blockade. Furthermore, when combined with surgery, αHSA-proIL-12 effectively prevented the postoperative recurrence and distant metastasis of advanced 4T1 tumors. This modular platform provides a clinically promising strategy to overcome the toxicity bottleneck of cytokines and substantially advances the development of combination cancer immunotherapies. Full article

Pantanal is the largest wetland on the American continent. This biome contains several plant species of interest for the development of medicines and cosmetics. Hence, this work aimed to review technologies described in patents concerning highly published plants from the Pantanal and their pharmacological and cosmetic applications. This research surveyed species in the Brazilian Pantanal and identified those with relevant scientific data. Patent searches for the selected species were conducted covering the past 10 years. Overall, 1859 plant and fungal species from the Pantanal were identified. Anacardium occidentale L., Annona montana Macfad., Annona muricata L., Annona squamosa L., and Calotropis procera (Aiton) W.T. Aiton presented the highest number of scientific publications. The patent search yielded 58 patents, mostly filed by private companies and in South Korea. Additionally, extracts were the primary products examined. The main pharmacological activities exploited were antitumoral, anti-inflammatory, and antidiabetic. For cosmetic compositions, the main activities were anti-aging, anti-acne, hair loss, and skin whitening. Despite strong scientific evidence for the included plant species, their claimed activities, and filings from Countries with a strong history of technology development, most studies focused on extracts. Therefore, the development of formulations to deliver these plant extracts is encouraged to improve technology transfer. Full article

L-type amino acid transporter 1 (LAT1), which controls the neutral amino acid uptake across the cell membranes, has been frequently overexpressed in various human cancers. Overexpression of LAT1 is associated with higher proliferation and shorter patient survival in tumors. Here, upregulated LAT1 expression was observed in patient-derived canine bladder cancers (BCs), and a small-molecule LAT1 inhibitor (JPH203) successfully reduced BC tumor growth both in vitro and in vivo. Patient-derived cancer cells were collected from dogs with naturally occurring tumors at veterinary clinics in Japan, and the 2.5D cancer organoid culture system was generated following our previous studies. Compared with other canine cancers or normal bladder cells, the increased LAT1 expression was observed in 2 strains of BC organoids. JPH203 inhibited boronophenylalanine (BPA) uptake activity by more than 90% and suppressed cell proliferation dose-dependently. Deprivation of BPA uptake activity by JPH203 also regulated the phosphorylation of mTOR-related proteins. Furthermore, intraperitoneal administration of JPH203 decreased the growth and tumor weight of BC organoid-derived xenograft in immunodeficient mice with an induction of apoptosis and a decrease in LAT1 expression compared to vehicle-administered mice. Therefore, the present study demonstrates that JPH203 exerts anti-tumor effects in canine BC through modulation of the mTOR signaling pathway and supports further investigation of LAT1-targeted therapy for canine BC. Full article

Soluble variants of recombinant T cell receptors (TCRs) have become attractive tools for the retargeting of cytotoxic T cells toward intracellular tumor or viral antigens by combining them with CD3-binding antibodies in bispecific T cell engagers; however, TCR-based NK cell engagers have not been studied so far. Here, we developed TCR-based bispecific agents for the redirection of NK cells utilizing a bivalent IgG1-like format. Trifunctional NK engagers included an Fc part with enhanced binding to FcγRIII/CD16A and single-chain (scFv) antibodies recognizing either NKp46 or CD16A, activating NK cell receptors. HCMV pp65/HLA-A2 reactive TCR-scFv-Fc fusion proteins incorporating an affinity-matured TCR and anti-NKp46 scFv activated peripheral blood NK cells and induced cytotoxicity in an antigen-specific manner. For T cell redirection, TCR-scFv-Fc fusion proteins included an scFv antibody recognizing CD3ε. Compared with NK cell engagers, T cell engagers showed similar sensitivity but lower peptide selectivity. For two TCRs recognizing melanoma-associated peptides, affinity-matured TCR-scFv-Fc fusion proteins enabled NK and T cell redirection and activation, and killing of tumor target cells loaded with exogenous peptides. Our results expand the versatility of the soluble TCR technology to NK cell engagers; however, they still require improvement in sensitivity to target tumor cells with low peptide/MHC-I complex densities. Full article

The efficacy of adoptive cell transfer (ACT) therapy in solid tumors is often limited by the functional exhaustion and insufficient persistence of infused CD8⁺ T cells within the tumor microenvironment. Through the integrated analysis of single-cell transcriptomic data, this study identified enolase 1 (ENO1), a key rate-limiting enzyme in glycolysis, as a core gene highly correlated with the superior anti-tumor phenotype of tumor-infiltrating lymphocytes (TILs). However, in vitro functional validation demonstrated that the overexpression of Eno1 failed to substantially enhance the anti-tumor efficacy of mouse T cells, suggesting the presence of a downstream metabolic regulatory node within the glycolytic cascade that restricts the conversion of carbon flux. To overcome this limitation, we introduced the small molecule activator TEPP-46 to target a crucial downstream metabolic hub, pyruvate kinase M2 (PKM2). Transcriptome sequencing confirmed that PKM2 activation successfully induced systemic metabolic rewiring in CD8⁺ T cells and broadly upregulated the expression of cytotoxicity- and memory-related genes. In an in vivo B16-OVA melanoma model, OT-1 T cells subjected to In vitro TEPP-46 pretreatment exhibited significantly enhanced tumor-suppressive capabilities and effectively promoted the preferential differentiation of T cells into central memory T cells (Tcm). In summary, this study highlights the importance of targeting downstream metabolic nodes to bypass intrinsic metabolic restrictions in T cells. It demonstrates that in vitro metabolic pretreatment via PKM2 activation represents an effective translational strategy for optimizing the anti-tumor efficacy of ACT cell products. Full article

Carbohydrates and their constituent monosaccharides have historically been viewed as metabolic substrates that provide cellular energy. However, recent evidence demonstrates that monosaccharides can also function as bioactive signaling molecules that affect immune responses through cellular metabolic reprogramming, post-translational protein glycosylation, receptor complex modulation, and transcriptional regulation of immune cell differentiation. These discoveries have given rise to the emerging concept of glyconutraceuticals, bioactive carbohydrates with therapeutic potential. This review discusses current evidence for the immunomodulatory properties of glucose, D-mannose, sialic acid, L-fucose, galactose, N-acetylglucosamine, D-xylose, and L/D-arabinose, with particular emphasis on their mechanisms of action in T cell activation, subset differentiation, metabolic reprogramming, and anti-tumor cytotoxicity. The context-dependent and often opposing effects of individual monosaccharides across T cell subsets underscore the complexity of immunomodulation by glyconutrients. Full article

Background: Antimitotic agents are very successful antitumor therapies, but lack tumor selectivity, causing toxicity. Antitumor alkylphospholipids (APLs) selectively accumulate in tumor cells but display low potencies. Hypothesis: Incorporating APL moieties onto antimitotic N-trimethoxyphenyl naphthalene sulfonamides (TMNS) might afford SMDCs with the potency of antimitotics and the tumor selectivity of APLs. Methods: 24 new TMNSs with spacers of different lengths (4 to 9 atoms) and nature (alkanes or ethers) on the sulfonamide nitrogen and capped with phosphorus-containing groups such as diethylphosphonates, phosphonic acids, and hydrogenophosphonate esters of aminoalcohols (diethylaminopropanol, choline, or dimethylaminoethanol) were designed and synthesized. Their antiproliferative effects against several cancer cell lines and their cotreatment with verapamil to assess whether they are substrates of MDR pumps were evaluated. The mechanism of action was studied: cell cycle effects, apoptosis induction, and immunofluorescence microscopy. Computational studies considered binding to tubulin and pharmacokinetics. Results: Diethyl phosphonates and phosphonic acids are antiproliferative in the micromolar to submicromolar range. P-gp inhibitor verapamil renders inactive compounds active, suggesting that efflux, not binding, removes activity. Mechanistic studies agree with an antimitotic action. Proposed binding to tubulin is similar to TMNS, with the phospholipid-like substituent projecting towards the interdimer space. Conclusions: Hybridization of TMNSs with potentially tumor–targeting APLs yields microtubule-disrupting antitumor compounds. However, the modifications assayed turn the compounds into substrates of MDR. These compounds are a proof of concept of the strategy that might succeed if future modifications avoid MDR and might target the compounds towards cancer cells. Full article

Objective: This study aimed to systematically evaluate the efficacy and safety of cadonilimab in the treatment of digestive system neoplasms. Methods: PubMed, Embase, Cochrane Library, Web of Science, Wiley Online Library, CNKI, Wanfang Data, CBM, and VIP databases were systematically searched to collect randomized controlled trials, non-randomized studies, and real-world studies investigating cadonilimab for the treatment of digestive system neoplasms. The initial search spanned from the inception of the databases to 4 February 2026, with an update search conducted in June 2026. Meta-analysis was performed using Stata 16.0 to systematically assess efficacy and safety outcomes. Results: A total of 10 studies, predominantly single-arm or retrospective, were included in this meta-analysis. Regarding the primary outcomes, because of the clinical heterogeneity across tumor types, pooled estimates should be interpreted as a summary across diverse diseases rather than as a single-tumor estimate. The overall pooled disease control rate (DCR) was 84% (95% CI = 76–91%), with tumor-specific DCRs of 87% in ESCC, 79% in HCC, 88% in G/GEJ adenocarcinoma, and 86% in PDAC. The pooled incidence of any-grade treatment-related adverse events (TRAEs) was 98% (95% CI = 95–100%), and the pooled incidence of any-grade immune-related adverse events (irAEs) was 32% (95% CI = 18–47%). For secondary outcomes: The partial response (PR) rate was 33% (95% CI = 21–46%), and the progressive disease (PD) rate was 11% (95% CI = 5–18%). The pooled incidence of grade ≥ 3 TRAEs was 52% (95% CI = 38–66%), and the pooled incidence of grade ≥ 3 irAEs was 11% (95% CI = 8–16%). However, incomplete reporting of low-frequency AEs across studies likely underestimates the pooled irAE rate. Conclusions: This study suggests that cadonilimab has the potential for antitumor activity in digestive system neoplasms. The observed safety profile was consistent with the known toxicities of immunotherapy, with notably high rates of TRAEs warranting vigilant monitoring. These findings should be considered hypothesis-generating and are insufficient to establish clinical benefit. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation. Full article

Background/Objectives: Vacuum-assisted breast biopsy (VABB) is widely used for the diagnosis of nonpalpable breast cancer but is not considered definitive treatment because microscopic residual disease may persist within or around the biopsy cavity. The ARTHE phase I trial evaluated a cavity-targeted radionuclide strategy based on same-session sequential intralesional administration of avidin followed by [⁹⁰Y]Y-DOTA-biotin after VABB. Methods: Eighteen women with nonpalpable breast cancer measuring ≤15 mm and a skin-to-cavity distance ≥ 13 mm were treated in three sequential activity-escalation cohorts. The primary objective was to assess acute local and systemic safety, including dose-limiting toxicity. The protocol-specified co-primary objective was to evaluate preliminary antitumor activity, assessed as breast-only pathologic complete response (pCR) at surgery. Given the phase I single-arm design, pCR was analyzed descriptively. The protocol-specified secondary objective was patient-specific dosimetry. Additional exploratory assessments included post-injection biodistribution and integration with subsequent breast-conserving surgery. Results: No dose-limiting toxicities, grade ≥ 3 adverse events, clinically relevant hematologic toxicity, treatment discontinuations, hospitalizations, or treatment-related surgical delays were observed. Local toxicity was limited to grade 1 injection-site pain and/or erythema. Post-injection imaging consistently demonstrated focal intralesional localization without clinically relevant extra-lesional uptake. All patients underwent breast-conserving surgery 4–7 weeks after treatment. No residual tumor cellularity (RTC), from either invasive or in situ carcinoma, was identified in the breast surgical specimen in 5/18 patients (27.8%). However, because diagnostic VABB may have removed part or all of the malignant lesion, the absence of residual carcinoma at surgery cannot be attributed specifically to the radionuclide treatment. Conclusions: The intralesional avidin-mediated local trapping strategy using [⁹⁰Y]Y-DOTA-biotin after VABB was feasible, showed favorable acute and short-term tolerability, was associated with early focal localization on post-injection imaging, and was compatible with standard breast-conserving surgery. Controlled studies are warranted to determine the therapeutic contribution of this post-biopsy cavity-targeted strategy, optimize administered activity, and refine patient selection. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, highlighting the urgent need for novel therapeutic strategies. This study aimed to identify bioactive small RNAs derived from Maytenus hookeri Loes. and evaluate their anti-tumor potential against non-small cell lung cancer (NSCLC). The 50 most abundant small RNAs were synthesized and screened in NCI-H460 cells using the MTS assay. Among them, MDM-sRNA-39 significantly inhibited cell viability and was selected for further evaluation of its anti-tumor activity. It reduced the percentage of cells that traversed the Transwell membrane and promoted apoptosis in NCI-H460 cells. Bioinformatics prediction suggested KRAS as a potential target of MDM-sRNA-39, and KRAS was among the targets experimentally validated by dual-luciferase reporter assays, RT-qPCR, and Western blot, showing that MDM-sRNA-39 suppresses KRAS expression at both mRNA and protein levels. In vivo, MDM-sRNA-39 was orally administered as a bencaosome in a Kras^LSL-G12D/p53^LoxP/LoxP autochthonous lung cancer mouse model. Tumor burden was reduced and cleaved caspase-3 staining was increased in the mouse model. Collectively, these findings identify MDM-sRNA-39, a synthetic small RNA based on a sequence identified from Maytenus hookeri Loes., as a candidate with anti-tumor activity, supporting the potential strategy for developing RNA-based therapeutics from traditional Chinese medicine. Full article

Anti-CD226 antibody-mediated stimulation of NK-92 cells (sNK-92) represents a potential immunotherapeutic approach; however, its cytotoxic and apoptosis-associated effects in hormone-independent solid tumors remain insufficiently characterized. This study investigated the activity of sNK-92 cells against PC3 castration-resistant prostate cancer and SH-SY5Y neuroblastoma cell lines, using PNT1A normal prostate epithelial and BJ normal dermal fibroblast cells as non-malignant controls. Cytotoxicity was assessed by CCK-8 assay at target-to-effector (T:E) ratios of 1:1, 1:5, and 1:10, and markers historically associated with the intrinsic (BAX, caspase-9), extrinsic (caspase-8), and executioner (caspase-3) apoptotic pathways were evaluated quantitatively by ImageJ-based corrected total cell fluorescence (CTCF) analysis. sNK-92 cells produced significant ratio-dependent cytotoxicity against PC3 and SH-SY5Y cells, reaching 23.76% and 26.29%, respectively, at the 1:10 T:E ratio, with sNK-92 producing significantly greater cytotoxicity than unstimulated NK-92 at this ratio in both cell lines and additionally at the 1:5 ratio in SH-SY5Y cells; no significant reduction in CCK-8 viability was detected in PNT1A or BJ cells at any ratio. Quantitative immunofluorescence analysis demonstrated substantially increased relative fluorescence intensity of all four apoptosis-associated markers in sNK-92-treated PC3 and SH-SY5Y cells compared with their corresponding controls and, in most comparisons, with NK-92-treated cells, whereas changes observed in the PNT1A and BJ non-malignant models examined were markedly smaller. These findings provide preliminary quantitative evidence that anti-CD226-stimulated NK-92 cells exert a preferential cytotoxic effect on the tumor cell models examined, relative to the non-malignant models tested, and induce changes in apoptosis-associated markers consistent with engagement of apoptotic signaling. Further orthogonal validation is warranted. Full article

To explore the emerging role of natural ligands, specifically coumarin and curcumin, and their coordination with the transition metals ruthenium (Ru) and iridium (Ir) as photosensitizers (PSs) in photodynamic therapy (PDT) for cancer. This highlights the integration of natural compounds and transition metals to overcome limitations in photophysical properties, hypoxia tolerance, and clinical translation. Regarding PDT oncology, this examines an immunological effect on Ru/Ir complexes and natural ligand-metal hybrids. They induce immunogenic cell death (ICD) through reactive oxygen species (ROS) generation, calreticulin exposure, extracellular ATP release, and HMGB1 secretion. These damage-associated molecular patterns act as “danger signals” to recruit dendritic cells, prime CD8⁺ cytotoxic T-cells, and establish systemic antitumor immunity. This study compares natural ligand-metal complexes with conventional Ru(II)/Ir(III) complexes and clinical PSs to assess their translational potential as immune-activating agents in PDT oncology, as well as focusing on the integration of nanotechnology with natural ligand-metal complexes to enhance delivery, biocompatibility, and clinical translation. A narrative review was conducted of the literature published between 2010 and 2025 across multiple electronic databases, including WanFang Data, PubMed, ScienceDirect, Scopus, Web of Science, Springer Link, SciFinder, and CNKI, without language restrictions. Studies focusing on coumarin, curcumin, Ru(II), Ir(III), and PDT were analyzed. Extracted data included chemical structures, absorption and emission spectra, singlet oxygen yields, biological activities, and therapeutic outcomes. Comparative evaluation was performed between free natural ligands, their Ru(II)/Ir(III) complexes, and nanodelivery systems to assess efficacy, biocompatibility, and translational potential. Coumarin and curcumin exhibited intrinsic antioxidant, anti-inflammatory, and anticancer properties but were limited by short absorption/emission ranges, poor photostability, and low singlet oxygen yields, restricting preclinical application. Coordination with Ru(II) and Ir(III) significantly enhanced intersystem crossing, extended absorption into the near-infrared region, and improved singlet oxygen quantum yields (Φ_Δ up to ~0.78). These complexes demonstrated potent photocytotoxicity under normoxia and hypoxia, achieving IC₅₀ values in the nanomolar range, which indicated organelle-specific targeting (mitochondria, lysosomes, ER), induced ICD, and synergized with checkpoint blockade. Nanocarrier encapsulation further improved solubility and tumor selectivity, and reduced systemic toxicity. Coumarin- and curcumin-based Ru/Ir complexes represent promising next-generation or immune activating PDT agents by combining natural pharmacological activity with superior photophysical performance. The ability to generate reactive oxygen species under hypoxia and achieve multimodal therapeutic effects positions them as strong candidates for clinical translation. Clinical approval of natural ligand-Ru/Ir complexes depends on rigorous safety, pharmacokinetic, and nanodelivery validation, but these complexes clearly extend PDT beyond local cytotoxicity toward durable immune protection. Future research should prioritize ligand engineering, nanotechnology integration, and translational models to bridge preclinical promise with safe and effective clinical applications. Full article