Search Results (75)

Phosphatidylserine (PS) externalization is a conserved membrane stress signal that becomes chronically dysregulated in cancer cells and tumor-associated endothelium. In vivo, PS does not exist as a free lipid signal but is presented in specific membrane-associated forms, including apoptotic or stressed cell surfaces, PS-rich extracellular vesicles, and circulating lipid particles. Unlike apoptosis-associated transient PS exposure, malignant PS externalization arises from metabolic rewiring, oxidative stress, epigenetic silencing of flippases, and microenvironmental cues, creating an immunosuppressive interface across the tumor–host boundary. This review synthesizes mechanistic, immunological, and clinical evidence on PS biology, including its roles in tumor immune evasion, extracellular vesicle-mediated systemic suppression, and vascular remodeling. We further summarize the development and evaluation of PS-targeted therapeutic platforms—such as bavituximab, SapC-DOPS/BXQ-350, and PS-directed imaging agents—and highlight their translational potential in combination with radiotherapy, chemotherapy, and checkpoint inhibitors. Chronic PS externalization, as manifested through distinct cellular and vesicular carriers, represents a unifying biomarker of tumor stress, immune suppression, and therapeutic vulnerability, offering a next-generation axis for theragnostic cancer management. Full article

Adoptive cell therapy (ACT) with T cells modified with a chimeric antigen receptor (CAR T cells) has dramatically improved outcomes in hematologic cancers. However, its efficacy in solid tumors, such as melanoma, is hampered by several factors. These include heterogeneous expression of tumor-associated antigens (TAA) and an immunosuppressive, profibrotic tumor microenvironment (TME), which restricts cytotoxic CAR T cells trafficking into the tumor, as well as their persistence and cytolytic activity. As a result, responses to CAR T cell monotherapy in melanoma and other solid tumors are typically weak, transient or even absent. Emerging evidence suggests that combining traditional chemotherapy with CAR T cell therapy can enhance the antitumor activity of CAR T cells in solid malignancies. Partial tumor cell killing by chemotherapy improves access to TAA and disrupts the TME by affecting the global structure of the tumor tissue. Here, we developed an immunocompetent syngeneic B16 melanoma mouse model to test a combination of classical dacarbazine (DTIC) chemotherapy with ACT with murine CAR T cells. B16-F10 (next as B16) melanoma cells were modified to express a human/murine hybrid epidermal growth factor receptor (EGFR) recognized by a murine CAR bearing a single-chain variable fragment (scFv) derived from cetuximab, an anti-EGFR monoclonal antibody approved for the treatment of colorectal and certain other solid tumors. Prior to CAR T cells administration, cyclophosphamide (CPA) pre-conditioning was used. We demonstrated that DTIC therapy followed by infusion of murine CAR T cells targeting the human/murine hybrid EGFR (EGFR mCAR T cells) provided superior tumor control and prolonged survival compared to monotherapy with either DTIC or EGFR mCAR T cells alone. These findings support the potential feasibility of a combined therapeutic strategy for human melanoma involving DTIC treatment followed by EGFR CAR T cells infusion after CPA pre-conditioning. Full article

Background: With the rising incidence of cancer, there is a growing need for improved preclinical models to test new therapies. While patient-derived xenografts (PDX) in immunodeficient mice are the gold standard, they are costly and result in a complete absence of a functional immune system, limiting their utility for studying tumor–immune interactions. This study characterizes a pharmacological partial immunosuppression protocol in immunocompetent mice as a promising alternative, evaluating its impact on the immune system and demonstrating its efficacy for growing human tumor xenografts. Methods: Mice received a regimen of cyclosporine (20 mg/kg, i.p., every 48 h for 12 days), cyclophosphamide (60 mg/kg, i.p., every 48 h for 8 days), and ketoconazole (10 mg/kg, p.o., for 12 days). The dynamics of CD3⁺, CD4⁺, CD8⁺, and CD19⁺ lymphocyte subpopulations and the CD4/CD8 index were monitored via flow cytometry on days 1, 5, 8, 12, 16, and 21. The protocol’s utility was tested by orthotopic transplantation of human glioma and lung cancer cells, and subcutaneous transplantation of breast cancer cells (MCF7). Tumor engraftment and growth were assessed using in vivo microscopy, MRI, and histology. Results: The immunosuppressive protocol induced a significant but partial reduction in CD3⁺ T-cells and CD19⁺ B-cells by day 8 (p = 0.0277). A profound and progressive decrease in the CD4/CD8 index was observed, indicating a shift towards immunosuppression. Crucially, CD8⁺ and CD4⁺ T-cells populations recovered rapidly post-therapy, demonstrating that the protocol creates a temporary and modifiable immune window rather than inducing complete ablation. The protocol enabled successful engraftment and growth of all three tested tumors in a residual immune microenvironment, confirmed by in vivo imaging and histopathological analysis. Conclusions: This drug-induced partial immunosuppression protocol effectively creates a reproducible state of transient immunodeficiency in outbred mice, suitable for various human tumor xenograft models. It represents a cost-effective and flexible alternative to genetic models, with the distinct advantage of preserving a residual immune microenvironment, making it particularly valuable for preclinical studies that require a partially intact host immune system. Full article

Background: Serological screening for HBV is standard in hemodialysis, and vaccination is recommended for non-immune patients. Objective: To determine the cause of positive HBsAg detected shortly after vaccination. Methods: We conducted a retrospective study in a tertiary hemodialysis unit. Patients with HBsAg reactivity after receiving the adjuvanted HBV vaccine (Fendrix^®) were followed with serial serology until HBsAg clearance. Results: Forty-four patients were monitored; seven (15.9%) tested HBsAg-positive 1–7 days post-vaccination, with no evidence of acute hepatitis, prior HBV infection, transplantation, or chronic immunosuppression. Six cleared HBsAg on repeat testing; one remained positive until day 19, with HBsAg as the only marker. Conclusions: Vaccine-related transient HBsAg antigenemia can occur shortly after immunization. Recognizing this phenomenon and timing routine serology appropriately can prevent misinterpretation and unnecessary workups in CKD patients. Full article

African swine fever virus (ASFV) poses a significant threat to the global pig industry due to high mortality rates and complex genetic variation. Live attenuated vaccines (LAVs) provide protection against ASFV. Previously, MGF505-2R was identified as a potent inhibitor of innate immunity in vitro. This study evaluates the pathogenicity of a recombinant Eurasian genotype II strain with the MGF505-2R gene deleted (ASFV-ΔMGF505-2R) in piglets. Twelve five-week-old crossbred piglets were divided into two groups, with one group of eight piglets inoculated with ASFV-ΔMGF505-2R (n = 8) and the other group of four piglets inoculated with the same dose of parental ASFV CN/GS 2018 (n = 4). Clinical symptoms, viral loads, and immune responses were monitored over 30 days. ASFV-ΔMGF505-2R-inoculated piglets exhibited transient fever and low viremia only in the beginning of the challenge, while the control group developed high levels of viremia and hyperthermia at day 2 and 8 post-challenge, respectively. Meanwhile, the control group demonstrated more severe post-mortem signs and immuno-histochemistry injury when compared to the ΔMGF505-2R group. ELISA analysis displayed higher levels of IFN-β and IL-1β in the ΔMGF505-2R group, further solidating the immunosuppressive role of MGF505-2R. All ASFV-ΔMGF505-2R-inoculated piglets developed high titers of ASFV-specific P30 antibodies at 10 days post-challenge. These findings rationalized the potential of ASFV-ΔMGF505-2R as a live attenuated candidate for ASF infection. Full article

This study evaluated whether iron supplementation in the form of chelated minerals in cows in the final third of lactation has a positive effect on iron bioavailability, immunity, oxidative status, milk quality, and biochemical and hematological parameters, as well as production efficiency and fecal microbiota. Twenty-four multiparous Jersey cows, with 210 ± 18 days in milk (DIM), an average production of 25 kg, and 4 ± 0.6 months of gestation, were divided into two groups: Control (n = 12, without supplementation) and Iron (n = 12, supplemented with 30 mg of iron/kg of dry matter (600 mg/animal/day)). Blood and milk samples were collected on days 1, 16, 29, and 42 of the experiment. Supplemented animals had higher serum iron concentrations and a higher unsaturated iron-binding capacity, especially on day 42. Higher iron content in milk was also observed. A higher granulocyte count was observed in the iron group, as well as a lower number of lymphocytes compared to the control, which may indicate immunosuppression associated with iron supplementation. Fructosamine levels were significantly lower in the iron group animals on days 14 and 28, suggesting a possible alteration in glucose metabolism. In contrast, levels of the liver enzymes AST and ALT increased significantly in the group supplemented with iron on days 28 and 42, indicating potential liver overload or injury. Iron supplementation significantly increased levels of reactive oxygen species and thiobarbituric acid-reactive substances, as well as superoxide dismutase activity in the blood. Iron supplementation altered gut microbial diversity, promoting dysbiosis characterized by increased alpha diversity and enrichment of transient colonization by Nitratireductor, Brevundimonas, Flavobacterium and Sporosarcina. Lower milk production was observed in the iron-supplemented cows in the last 10 days of the experiment, which is related to the occurrence of disease in nine cows in this group: seven with mastitis and two with intestinal peristalsis paralysis. Based on these results, we conclude that chelated iron supplementation at a dose of 600 mg/animal/day should not be used because it harms cow health and productivity. Full article

Background: Severe traumatic brain injury (TBI) often leads to elevated intracranial pressure (ICP) that requires aggressive management. Inducing burst suppression with deep sedation is an established therapy for refractory intracranial hypertension. Traditionally, barbiturate coma has been used to achieve burst-suppression EEG in TBI patients, but alternative sedative agents (propofol, midazolam, ketamine, dexmedetomidine) are increasingly utilized in modern neurocritical care. This review compares barbiturates with these alternatives for inducing burst suppression in adult TBI, focusing on protocols, mechanisms, efficacy in controlling ICP, safety profiles, and impacts on neurological outcomes. Methods: A search of the literature was performed, including clinical trials, observational studies, and guidelines on deep sedation for ICP control in adult TBI. Studies comparing high-dose barbiturates to other sedatives (propofol, midazolam, ketamine, dexmedetomidine) in the context of burst suppression or severe TBI management were included. Data on sedative protocols (dosing and EEG targets), mechanisms of action, ICP-lowering efficacy, complications, and patient outcomes were extracted and analyzed qualitatively. Results: High-dose barbiturates (e.g., pentobarbital or thiopental) and propofol are both effective at inducing burst-suppression EEG and reducing ICP via cerebral metabolic suppression. Barbiturate coma remains a third-tier intervention reserved for ICP refractory to other treatments. Propofol infusion has become first-line for routine ICP control due to rapid titratability and shorter half-life, though it can also achieve burst suppression at high doses. Midazolam infusions provide sedation and seizure prophylaxis but yield less metabolic suppression and ICP reduction compared to barbiturates or propofol, and are associated with longer ventilation duration and delirium. Ketamine, once avoided for fear of raising ICP, has shown neutral or lowering effects on ICP when used in ventilated TBI patients, thanks to its analgesic properties and maintenance of blood pressure; however, ketamine alone does not reliably produce burst-suppression patterns. Dexmedetomidine offers sedative and anti-delirium benefits with minimal respiratory depression, but it is generally insufficient for deep burst-suppressive sedation and has only a modest effect on ICP. In comparative clinical evidence, propofol and barbiturates both effectively lower ICP, but neither has demonstrated clear improvement in long-term neurological outcome when used prophylactically. Early routine use of barbiturate coma may increase complications (hypotension, immunosuppression), and thus, current practice restricts it to refractory cases. Modern sedation protocols emphasize using the minimal necessary sedation to maintain ICP < 22 mmHg, with continuous EEG monitoring to titrate therapy to a burst-suppression target (commonly 2–5 bursts per minute) when deep coma is employed. Conclusions: In adult TBI patients with intracranial hypertension, propofol-based sedation is favored for first-line ICP control and can achieve burst suppression if needed, whereas high-dose barbiturates are reserved for ICP crises unresponsive to standard measures. Compared to barbiturates, alternative agents (propofol, midazolam, ketamine, dexmedetomidine) offer differing advantages: propofol provides potent, fast-acting metabolic suppression; midazolam adds anticonvulsant sedation for prolonged use at the cost of slower wake-up; ketamine supports hemodynamics and analgesia; dexmedetomidine aids lighter sedation and delirium control. The choice of agent is guided by the clinical scenario, balancing ICP reduction needs against side effect profiles. While all sedatives can transiently reduce ICP, careful monitoring and a tiered therapy approach are essential, as no sedative has conclusively improved long-term neurological outcomes in TBI. EEG monitoring for burst suppression and meticulous titration is required when employing barbiturate or propofol coma. Ongoing research into optimal combinations and protocols may further refine sedation strategies to improve safety and outcomes in severe TBI. Full article

Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy by enhancing T-cell-mediated anti-tumor responses in solid malignancies. However, their efficacy is often limited by tumor-specific factors, T-cell dysfunction in cold tumors, or in the presence of lymph node metastasis (LNM). Moreover, clinical trials indicate no significant survival advantage of sentinel lymph node biopsy (SLNB) over no lymph node surgery in early-stage cancers, highlighting the need for novel combinatorial approaches to improve treatment outcomes. Tumor electrochemotherapy (ECT) can overcome immunosuppressive barriers in the tumor microenvironment by applying high electric fields that create transient micropores in cell membranes. This allows the enhanced uptake of chemotherapeutic drugs, resulting in increased cytotoxicity and the release of damage-associated molecular patterns (DAMPs). This triggers immunogenic cell death (ICD), a process that signals immune cells to attack cancer and promotes tumor regression. Considering advancements in lymphatic-targeted therapies and the immunostimulatory potential of uninvolved tumor-draining lymph nodes (TDLNs), TDLN-targeted ECT may act as an in situ cancer vaccination, activating immune cells within TDLNs through the release of DAMPs and serving as a hub to orchestrate systemic anti-tumor immunity. In patients with negative preoperative lymph node assessments, this approach may preserve lymph node integrity and lymphatic drainage while eradicating tumor cell colonies. When applied as neoadjuvant therapy before any TDLN treatment, TDLN-targeted ECT may leverage higher tumor-associated antigen loads, foster persistent immune memory, and reduce the risk of post-operative immune evasion. Full article

Background: Exercise-induced bronchoconstriction (EIB) is common in athletes, being more frequent in outdoor endurance-based/long-distance sports. We followed a World-Class marathon paddler’s season with recurrent episodes of EIB, which intensified during cold exposure workouts. This unique immunophenotype profile during the season and its variations were reflected in acute and chronic inflammatory markers. Methods: A longitudinal case study was conducted with blood sampling obtained from a single paddler after overnight fasting at three timepoints: T1 (beginning of season, after 15-day rest period), T2 (post-Winter National Championship), and T3 (post-Summer National Championship). Complete blood counts and lymphocyte immunophenotyping were performed using automated hematology analysis and multiparametric flow cytometry. Results: The total numbers of leukocytes (T1: 6.3; T2: 5.0; T3: 5.5 × 10⁹/L), neutrophils (3.1; 2.5; 2.8 × 10⁹/L), and lymphocytes (2.4; 1.8; 2.2 × 10⁹/L) declined between T1 and T2, followed by a partial recovery at T3. In contrast, monocyte counts exhibited the reverse pattern (0.41; 0.62; 0.31 × 10⁹/L). The two T cell subsets (αβ and γδ) remained relatively stable, showing only minor seasonal fluctuations. CD19+ B cells, initially at very low levels, increased steadily as the season progressed (0.05; 0.07; 0.16 × 10⁹/L). During T2, the proportion of memory lymphocytes (CD45RO+) rose, while naive cells (CD45RA+) declined; this trend was subsequently inverted at M3. Although the CD4+/CD8+ ratio varied over time, it consistently stayed below the normal reference range established for healthy controls (0.50; 0.83; 0.60 for T1, T2, and T3, respectively). Conclusions: The immune assessment of the World-Class marathon paddler revealed transient immunosuppression early in the season, marked by reduced neutrophils, a low CD4+/CD8+ ratio, and diminished CD19+ lymphocytes. Over time, immune parameters showed signs of recovery, indicating a temporary imbalance that did not impair the athlete’s physical performance. Conclusions: This case study of an elite marathon kayaker revealed transient immune fluctuations across a competitive season, including early immunosuppression (low neutrophils, CD4+/CD8+ ratio 0.50, and minimal CD19+ B cells) followed by partial recovery mid- and late-season. Despite persistently inverted CD4+/CD8+ ratios suggesting chronic immune dysregulation, the athlete maintained competitive performance, highlighting the temporary nature of these changes and emphasizing that regular immune monitoring can help optimize health and performance in elite athletes. Full article

Minimally invasive surgery is known to lessen postoperative stress and complications compared with open procedures, yet its molecular effects on immunity and cancer-related mechanisms remain unclear. This study examined immune and inflammatory responses after robot-assisted (RS) versus open (OS) colorectal cancer surgery. Sixty-one patients (RS = 30; OS = 31) were enrolled. Blood samples were collected before surgery and at 8, 24, and 72 h post-incision. Cytokines, growth factors, and prostanoids were measured using multiplex immunoassays and mass spectrometry to assess systemic immune and inflammatory changes. Surgery type markedly influenced perioperative immune profiles. RS induced stronger activation of Th1-associated cytokines, including IFNγ and IP-10, suggesting enhanced cellular immune responsiveness. In contrast, Th2 cytokines and other immunosuppressive mediators—such as IL-4, IL-10, and G-CSF—showed smaller or transient increases after RS, whereas OS triggered broader and more sustained elevations. Angiogenic factors (VEGF-A, PDGF-BB, FGF2) rose significantly after OS but remained comparatively lower and returned to baseline faster after RS, indicating a weaker proangiogenic response. Similarly, postoperative surges in prostaglandins linked to inflammation and tumor progression (PGE₂, PGF₂α) were blunted and resolved earlier following RS. Overall, the robotic approach was associated with reduced inflammatory and immunosuppressive activity, faster recovery of immune balance, and diminished biochemical signals favoring angiogenesis and potential tumor regrowth, suggesting a potential protective effect against pathogens and cancer-promoting mechanisms after colorectal tumor resection. Full article

Background: The liver’s role as a metabolic gatekeeper positions it uniquely to influence systemic metabolic homeostasis and potentially modulate leukemogenesis through hepato-hematopoietic crosstalk. Recent observations of rare hematological malignancies following mRNA vaccination warrant mechanistic investigation. Hypothesis: We propose that mRNA vaccines, through their preferential hepatic tropism via lipid nanoparticles (LNPs), may transiently dysregulate hepatic metabolism in susceptible individuals, creating metabolic perturbations that amplify pre-existing leukemogenic vulnerabilities through five interconnected mechanisms: (1) competitive folate sequestration for vaccine-induced lymphoproliferation, potentially starving bone marrow precursors of essential one-carbon units; (2) hepatic lipid processing overload from LNP accumulation, exacerbating phospholipid dysregulation in pre-leukemic clones; (3) cytokine-mediated upregulation of hepatic indoleamine 2,3-dioxygenase (IDO), accelerating tryptophan catabolism and creating an immunosuppressive milieu favoring leukemic escape; (4) inflammatory induction of hepcidin, sequestering hepatic iron while triggering compensatory intestinal iron hyperabsorption and potential bone marrow iron overload; and (5) increased hepatic NADPH demand for antioxidant defense and lipid metabolism, diverting reducing equivalents from bone marrow stromal support. Implications: This hypothesis suggests that transient hepatic metabolic perturbations may create a permissive milieu for leukemogenesis in metabolically vulnerable individuals. The proposed mechanisms generate testable predictions and identify potential therapeutic targets, including folate supplementation, IDO inhibition, and iron chelation in high-risk cohorts. Full article

Oral leukoplakia (OL) is the most common potentially malignant oral disorder, with variable risk of progression to oral squamous cell carcinoma (OSCC). This study evaluated the chemopreventive and immunomodulatory potential of Artemisinin (ART) and Rubus occidentalis (RO), alone or combined (ARO), in a 4NQO-induced murine model. Mice received 4NQO (100 µg/mL) in drinking water, and treatments began at week 8. Animals were euthanized at weeks 12 and 16 for histological, apoptotic (caspases-3, -8, -9; calreticulin), inflammatory (IL-1β, IL-10, HMGB1), and immune (CD8, CD68, CD56, IFN-γ, GM-CSF) marker analyses. RO-treated animals showed delayed malignant transformation, with no carcinomas at week 16 and increased expression of caspase-9, calreticulin, HMGB1, IFN-γ, and GM-CSF, indicating transient activation of antitumor immune responses. ART-treated mice showed increased CD68 and reduced CD56 expression, suggesting an immunosuppressive profile and higher carcinoma incidence. The ARO combination did not improve outcomes beyond ART alone. These findings support the immunomodulatory and pro-apoptotic effects of RO in delaying OL progression, highlighting its chemopreventive potential. ART showed limited benefit under current conditions, warranting further investigation into dose optimization and synergistic strategies. Full article

Background/Objectives: The growing prevalence of metabolic-associated steatotic liver disease (MASLD)/metabolic-associated steatohepatitis (MASH) is forecasted to be over 55% by 2040, representing a significant driver of cirrhosis and highlighting demand for effective therapeutic interventions. The therapeutic landscape is evolving with agents, like glucagon-like peptide-1 receptor agonists (GLP-1 RAs), under active investigation. A common concern across emerging therapies is potentially precipitating decompensation in patients with existing cirrhosis, necessitating careful consideration in this population. Case Presentation: A 46 y.o. female with obesity and cirrhosis from MASH and alcohol who underwent a deceased-donor liver transplant developed steatohepatitis within a year post-transplant after gaining 36 kg. Transient elastography revealed controlled attenuation parameter (CAP) 400 dB/m (S3 steatosis) and liver stiffness measurement (LSM) 61.2 kPa (advanced fibrosis). Follow-up biopsy confirmed severe steatohepatitis (NAS 7/8) and advanced fibrosis (F3), attributed to metabolic dysfunction without evidence of alcohol recurrence. She decompensated with ascites and varices, leading to transplant re-enlistment at MELD-Na 29. Despite two years of intensive lifestyle modification, losing 17 kg, and recompensation, her follow-up elastography showed persistent steatosis (S3) and advanced fibrosis (F4). Subsequent allograft biopsy revealed progression to cirrhosis (F4) with ongoing steatohepatitis (NAS 3/8). Tirzepatide was initiated for the development of type 2 diabetes, attributed to steroids used for immunosuppression. After 2 years on tirzepatide, she lost 43.1 kg. Shockingly, her follow-up elastography demonstrated fibrosis regression with LSM 5.5 kPa (F1) and steatohepatitis resolution with CAP 204 dB/m (S0). Follow-up liver biopsy confirmed fibrosis regression to F2-F3 and steatohepatitis resolution (NAS 1/8). Conclusions: This case challenges the widely accepted dogma that liver MASH cirrhosis is irreversible. Using multiple liver fibrosis monitoring modalities, cirrhosis reversal was demonstrated and attributed to mechanisms of GLP-1/GIP RA therapy. This study suggests that GLP-1/GIP RA may be safe in cirrhosis and may result in fibrosis regression. Full article

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis and obstetric complications, driven by antiphospholipid antibodies (APLAs). This review synthesizes the latest advancements and current understanding, diagnosis, and treatment of APS. APLAs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2-GPI), interfere with coagulation and endothelial function, as well as with placental health. APS can be primary or secondary; it is often associated with systemic autoimmune diseases like lupus. The pathogenesis of APS remains only partially understood. APLAs promote thrombosis through endothelial damage, platelet activation, and inflammatory signaling pathways. Laboratory diagnosis relies on persistent positivity for APLAs and LAC through tests like ELISA and clotting assays, following a three-step confirmation process. New integrated test systems have been introduced to improve standardization. Classification criteria have evolved, with the 2023 EULAR-ACR criteria providing a weighted, domain-based scoring system, enhancing diagnostic precision. Catastrophic APS (CAPS) is a severe, rare manifestation of APS, characterized by multi-organ failure due to rapid, widespread microthrombosis and systemic inflammation, which requires urgent anticoagulation. Seronegative APS is proposed for patients with clinical features of APS but negative standard antibody tests, possibly due to non-criteria antibodies or transient immunosuppression. Treatment primarily involves long-term anticoagulation with vitamin K antagonists; direct oral anticoagulants are generally not recommended. APS diagnosis and management remain complex due to clinical heterogeneity and laboratory challenges. Continued refinement of diagnostic tools and criteria is essential for improving outcomes in this life-threatening condition. Full article

The Gliomas account for 81% of all malignant central nervous system tumors and are classified by WHO into four grades of malignancy. Glioblastoma multiforme (GBM), the most common grade IV glioma, exhibits an extremely aggressive phenotype and a dismal five-year survival rate of only 6%, underscoring the urgent need for novel therapeutic approaches. Immunotherapy has emerged as a promising strategy, and photodynamic therapy (PDT) in particular has attracted attention for its dual cytotoxic and immunostimulatory effects. In GBM models, PDT induces immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs), which promote antigen presentation and activate T cell responses. Additionally, PDT transiently increases blood–brain barrier permeability, facilitating immune cell infiltration into the tumor microenvironment, and enhances clearance of waste products via stimulation of meningeal lymphatic vessels. Importantly, PDT can reprogram or inactivate immunosuppressive tumor-associated macrophages, thereby counteracting the pro-tumoral microenvironment. Despite these encouraging findings, further preclinical and clinical studies are required to elucidate PDT’s underlying immunological mechanisms fully and to optimize treatment regimens that maximize its efficacy as part of integrated immunotherapeutic strategies against GBM. Full article