Search Results (3,273)

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

Nanomedicine has yielded clinically useful platforms, including liposomes, albumin-bound nanoparticles, and lipid nanoparticles; yet, many systems translate poorly because of nonspecific biodistribution, limited target-site accumulation, inefficient cellular uptake and intracellular delivery, immune clearance, and off-target toxicity. These bottlenecks are often shaped at cell membrane interfaces, where therapeutic materials are recognized, retained, internalized, or cleared and may elicit unsafe responses. Here, we frame cell membrane biophysics as a therapeutic interface for nanomedicine. We examine how lipid organization and fluidity, mechanics, electrochemical state, glycocalyx architecture, and membrane protein identity shape recognition, adhesion, endocytosis, fusion, trafficking, immune responses, and drug release. We assess how disease-associated membrane remodeling can create candidate therapeutic entry points and delivery barriers across cancer, neurodegeneration, inflammation, infection, and vascular disease. We then analyze receptor-mediated targeting, lipid-domain-associated uptake, membrane-coated nanocarriers, engineered extracellular vesicles, and hybrid platforms, with explicit context-of-use definitions and design boundaries. Finally, we propose translational qualification through function-linked critical quality attributes, mechanism-relevant potency assays, context-matched models, in vivo pharmacology and immune safety, scalable manufacturing, and regulatory evaluation. Progress will depend less on descriptive membrane mimicry than on measurable, reproducible, and qualified membrane-dependent functions. Full article

Gastric cancer is one of the malignancies with the highest incidence and mortality worldwide. Helicobacter pylori (H. pylori) infection is the primary driving factor in its development. The progression of gastric mucosal malignancy follows the Correa cascade model: “chronic non-atrophic gastritis → chronic atrophic gastritis (CAG) → intestinal metaplasia (IM) → dysplasia (Dys) → gastric cancer.” Currently, clinical management faces major challenges, including increasing antibiotic resistance in H. pylori, limited pharmacological options for gastric precancerous lesions, and treatment resistance and toxicity in established gastric cancer. This review synthesizes current evidence on BBR, COP, EPI, PAL, and JAT and organizes their reported actions into a three-tier intervention framework. At the first tier, etiologic and inflammatory interception, individual alkaloids suppress H. pylori persistence through direct antibacterial injury, urease inhibition, and modulation of bacterial virulence and antibiotic susceptibility, while attenuating infection-driven inflammatory and immune responses. At the second tier, modulation of precancerous mucosal progression, preclinical studies indicate that these compounds can ameliorate gastric glandular injury and may attenuate biological processes associated with progression toward intestinal metaplasia and dysplasia. At the third tier, antitumor and adjunctive intervention in established gastric cancer, alkaloids inhibit proliferation, induce cell-cycle arrest and apoptosis, suppress invasion and metastasis, and regulate non-coding RNA and epigenetic networks; BBR-centered preclinical studies further suggest potential chemosensitizing and supportive effects. This review integrates the five alkaloids BBR, COP, EPI, PAL, and JAT and systematically elucidates their mechanisms of action across the pathological continuum from H. pylori infection and chronic inflammation to precancerous lesions and ultimately gastric cancer. It establishes a stage-oriented, compound-specific analytical framework to clarify the pharmacological positioning of these compounds, identify priorities requiring further validation, and guide future mechanistic and translational research. Full article

Protease-activated receptor-2 (PAR-2; encoded by F2RL1) is emerging as a context-dependent driver of gastrointestinal cancer. Activated by irreversible N-terminal cleavage, its signalling output is not fixed but is calibrated by the identity and source of the activating protease, the receptor cleavage state, cellular context and biased coupling to G-protein αq (Gαq), G-protein α12/13 (Gα12/13) and β-arrestin. PAR-2 is best understood not as a simple inflammatory receptor but as a proteolytic rheostat that converts diverse coagulation, inflammatory, microbial and stromal protease inputs into distinct oncogenic programmes. Colorectal cancer and pancreatic ductal adenocarcinoma provide complementary models: in colorectal cancer, PAR-2 links mucosal inflammation and coagulation to proliferation, metastatic competence and resistance to epidermal growth factor receptor (EGFR)-targeted therapy, whereas in pancreatic cancer, it is embedded in a tissue-factor-rich desmoplastic microenvironment that promotes invasion, immune exclusion and chemoresistance. Therapeutic strategies suggested by this framework include direct and biased PAR-2 modulators, upstream protease and factor Xa (FXa) inhibition, statin repurposing and activated-fragment biomarkers such as the PAR-2 activation neoepitope (PRO-PAR2). These strategies must be applied under biomarker guidance, since PAR-2 blockade may benefit inflammation-dominant tumours yet prove counterproductive where PAR-2 sustains antitumour immunity. Full article

Colorectal cancer (CRC) progression is shaped by dynamic interactions between tumor-intrinsic metabolic adaptations and immune remodeling within the tumor microenvironment. In CRC, the expression of SMAD7, a classical inhibitor of TGF-β1 signaling, is increased and has been associated with tumor-associated inflammatory responses and malignant progression. In this study, we investigated the potential role of SMAD7 in regulating glycolytic metabolism and macrophage phenotype in CRC. Knockdown of SMAD7 in CRC cell lines resulted in reduced glycolytic activity, as demonstrated by decreased extracellular acidification rate, basal glycolysis, and glycolytic capacity. These metabolic changes were associated with reduced expression of the basal and IL-6- and IL-22-induced glycolytic enzyme hexokinase 2 (HK2), while glucose uptake was increased. Similar reductions in HK2 expression were observed in patient-derived CRC organoids following SMAD7 inhibition, supporting the relevance of this pathway in human tumor-derived models. Functionally, SMAD7 knockdown reduced lactate production by CRC cells and diminished the ability of tumor cell-derived conditioned medium to induce the expression of macrophage-associated immunoregulatory markers, including CD163, CD206, and ARG1. The addition of exogenous lactate restored these effects, indicating that tumor-derived lactate contributes to SMAD7-dependent control of the expression of macrophage-associated immunoregulatory markers. Analysis of human CRC transcriptomic datasets revealed positive associations between SMAD7 expression and macrophage-related signatures, including profiles associated with immunoregulatory tumor-associated macrophages. Together, these findings support a potential role for SMAD7 in controlling tumor metabolism and macrophage-associated immunoregulatory markers in CRC. Full article

Background and Objectives: Ovarian cancer remains the most lethal gynecologic malignancy, largely due to late diagnosis and the limitations of currently available diagnostic tools. Systemic inflammatory markers derived from routine blood tests have emerged as potential low-cost biomarkers, reflecting the interaction between tumor biology and the host immune response. This study aimed to evaluate the association and diagnostic value of preoperative inflammatory markers in distinguishing malignant from non-malignant ovarian tumors. Materials and Methods: This retrospective, single-center observational study included 780 adult female patients diagnosed with ovarian tumors and treated surgically between January 2020 and December 2025. Preoperative hematological parameters were obtained from complete blood count analyses performed before any therapeutic intervention. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were calculated. Comparisons were performed among benign, borderline, and malignant tumors. To avoid collinearity between mathematically interrelated inflammatory indices, three separate multivariable logistic regression models were constructed, each including age, CA-125, and one inflammatory index. Diagnostic performance of the individual inflammatory indices was assessed using receiver operating characteristic (ROC) curve analysis. Results: Patients with malignant tumors were significantly older and exhibited higher NLR and PLR values and lower LMR values than patients with non-malignant tumors (all p < 0.001). In separate multivariable models adjusted for age and CA-125, higher NLR (OR = 1.79, 95% CI: 1.41–2.27, p < 0.001) and PLR (OR = 1.43, 95% CI: 1.17–1.75, p = 0.001) remained significantly associated with malignant ovarian tumors, whereas higher LMR was inversely associated with malignancy (OR = 0.66, 95% CI: 0.52–0.85, p = 0.001). ROC analysis demonstrated moderate discriminative ability for NLR and PLR (AUC = 0.72 for both), whereas LMR showed lower discriminative performance (AUC = 0.64). Conclusions: Preoperative systemic inflammatory indices are significantly associated with ovarian tumor malignancy. NLR and PLR were positively associated with malignant disease, whereas LMR showed an inverse association, and these relationships remained significant after adjustment for age and CA-125. However, their individual discriminative performance was modest, suggesting that these readily available inflammatory indices should be considered complementary rather than standalone biomarkers for preoperative risk assessment. Full article

Breast cancer (BRCA) possesses prominent molecular heterogeneity, where aberrant expression of genes annotated to asparagine metabolism networks drives malignant progression and therapeutic resistance. However, systematic construction of prognostic signatures from a holistic asparagine metabolic pathway perspective remains scarce, limiting the clinical translation of metabolic insights into prognostic tools. We integrated TCGA and GEO BRCA transcriptomic datasets to screen asparagine metabolism-related differentially expressed genes and build a prognostic model. Six biomarkers, SLC35A2, SRD5A2, NT5E, CEL, IFNG and CNR1, were selected via univariate Cox, LASSO and multivariate Cox regression. SRD5A2 and IFNG were enriched in low-risk patients, while the other four genes were upregulated in high-risk subgroups. This signature reliably stratifies patient prognosis, with risk scores correlating strongly with pathway activity, immune infiltration, immune checkpoints, mutation landscapes and drug responsiveness. Bioinformatic results were validated via TCGA cohort analysis, in vitro cellular assays and Western blot. Two in vivo models were established: 4T1 xenografts in 6-week-old BALB/c mice and DMBA/hormone-induced spontaneous breast tumors in 8-week-old SD rats. Tumors were generated by cell injection or DMBA gavage plus cyclic hormone treatment, and tissue sections were processed for immunohistochemistry. Consistent differential expression of the six core genes was validated across all in vitro and in vivo systems. In conclusion, this asparagine metabolism-associated signature offers candidate biomarkers for personalized prognosis and provides preclinical evidence for metabolism-targeted BRCA therapy. Full article

A standardized extract of cultured Lentinula edodes mycelia (ECLM), commercially known as AHCC^®, shows anti-inflammatory, immunomodulatory, and organ-protective properties. Experimental studies have indicated that ECLM modulates innate and adaptive immunity, including natural killer (NK) cell activity, antigen-presenting cell function, T-cell responses, and cytokine balance. These effects are particularly relevant in oncology because surgical stress and ischemia–reperfusion injury (IRI) generate a transient perioperative environment characterized by immune suppression, inflammation, and conditions favorable for metastatic progression. Recent animal studies have demonstrated the protective effects of ECLM in intestinal and hepatic IRI models, providing a potential mechanistic rationale for improving the perioperative host microenvironment. Clinical studies on hepatocellular carcinoma, pancreatic cancer, and gynecological malignancies suggest that ECLM may offer potential benefits in immune preservation, nutritional support, symptom management, and recurrence prevention, although most studies are small and hypothesis-generating. Emerging evidence from patient-derived xenograft and spontaneous carcinogenesis models further suggests that ECLM may influence tumor biology beyond host immune activation, although the underlying mechanisms require elucidation. This review summarizes the mechanistic, preclinical, translational, and clinical evidence supporting the use of ECLM as a candidate for perioperative immunonutritional strategies. We propose the hypothesis that ECLM may function as a perioperative microenvironmental stabilizer that integrates immune preservation and intestinal barrier protection. Full article

Background: The interaction between COVID-19 vaccination and immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC) remains incompletely characterized. Methods: Retrospective cohort study of 139 patients with stage IV NSCLC treated with first-line ICI-based therapy, stratified by vaccination status and total doses received (0–1 vs. ≥2). Progression-free (PFS) and overall survival (OS) were analyzed by Kaplan–Meier and Cox regression; logistic regression explored factors associated with treatment-related toxicity. Results: Vaccinated patients had longer median PFS (13.0 vs. 11.0 months) and OS (29.0 vs. 24.0 months; both p < 0.001). In multivariable models these associations were attenuated and of borderline significance (OS HR = 0.83, 95% CI 0.69–0.99; PFS HR = 0.79, 95% CI 0.62–0.99). Outcomes were also more favorable with ≥2 doses (median PFS 14.0 vs. 12.0 months, p = 0.001; median OS 30.0 vs. 24.0 months, p < 0.001), and tumor mutational status was the strongest independent predictor of survival. In an exploratory model, ≥2 doses were associated with higher odds of any-grade toxicity (OR = 2.47, p = 0.037); events were predominantly low grade, with no Grade 4 or 5 toxicity. Conclusions: COVID-19 vaccination was associated with improved PFS and OS in stage IV NSCLC receiving first-line ICI therapy, with a dose-related pattern. The association was attenuated after adjustment for tumor biology and is hypothesis-generating. These findings support the safety and potential clinical relevance of vaccination in this population and underline the need for structured monitoring during immunotherapy. Prospective validation is required. Full article

In 1909, Paul Ehrlich first suggested that the immune system is critical for suppressing carcinogenesis and cancer growth, which led to the introduction of cancer immunosurveillance by Sir MacFarlane Burnet in 1960. Burnet’s cancer immunosurveillance was further supported and elaborated by Thomas Lewis in 1982, who noted, for example, the limitations of investigating cancer immunosurveillance in available experimental models, except for virus-induced cancers. The concept of cancer immunosurveillance in 2001 was revised to cancer immunoediting (the immunoediting term was introduced by Dr. Rober Schreiber), based on findings that the immune system not only controls tumorigenesis and tumor growth but also tumor quality/grade or immunogenicity. Advances in immunology, including the identification of target organs and the local immune system, and the identification of novel innate immune cells regulating the adaptive immune response, have further advanced the understanding of cancer immunosurveillance and immunoediting. The current article discusses the evolution of the cancer immunosurveillance hypothesis into cancer immunoediting. At the time of the introduction of cancer immunoediting, the direct role of dendritic cells (DCs) in tumor immunity and immunoediting was not much explored. Similarly, the concept of tumor-associated macrophages (TAMs) and their role in cancer immunosurveillance and immunoediting was not much studied. The current article discusses the evolution of DCs and TAMs in the context of tumor immunity, cancer immunoediting, and immunotherapies specifically targeting these innate immune cells. Full article

Chronic diseases and aging-related disorders are driven by interconnected mechanisms, including oxidative stress, low-grade inflammation, metabolic dysregulation, and glycation. Targeting these overlapping pathways remains a major challenge for conventional single-target therapeutics. In this context, endophytic fungi have emerged as a promising source of bioactive metabolites with multi-target pharmacological potential. This review provides a mechanistic overview of endophyte-derived metabolites, including alkaloids, terpenoids, polyketides, and phenolic compounds, with a focus on their ability to modulate key signaling pathways such as NF-κB, Nrf2, PI3K/Akt, AMPK, and the AGE–RAGE axis. Evidence from experimental studies suggests that these metabolites exhibit anticancer, anti-inflammatory, antioxidant, and metabolic regulatory effects through coordinated modulation of cellular signaling networks. Several endophyte-derived metabolites also possess antimicrobial activity against bacterial and fungal pathogens and may represent a promising source of novel anti-infective agents. Their ability to modulate host immune responses and microbial-associated signaling pathways further highlights their relevance for antimicrobial discovery and microbiome-based therapeutic strategies. Particular attention is given to pathway-level convergence in chronic diseases, including cancer, diabetes, and inflammation-associated disorders, as well as their relevance to aging and health span. The pharmacological potential of these compounds is discussed alongside key limitations, including issues related to bioavailability, reproducibility, and translation into clinical applications. Overall, endophytic fungal metabolites represent a structurally diverse and mechanistically rich resource for the development of multi-target therapeutic strategies. Future integration of metabolomics, genome mining, and advanced disease models will be essential to bridge the gap between experimental findings and clinical application. Full article

Background/Objectives: Human papillomavirus (HPV)-associated cancers remain a major global health burden, and no therapeutic cancer vaccine has yet been approved. Oncoprotein E7 plays a key role in tumor initiation and progression and has been identified as a potential target. Here, we aim to improve the efficacy and durability of an outer membrane vesicle (OMV)-based E7-targeted vaccine, SOMV-9RE7, through alb-Flt3L combination therapy. Methods: The antitumor efficacy and durability of the combination therapy were evaluated in low-burden and high-burden HPV-positive TC-1 tumor-bearing mouse models. Systemic and local immune responses were investigated by flow cytometry. Results: Combination with alb-Flt3L improved the tumor control and prolonged the therapeutic durability of SOMV-9RE7 compared with monotherapy groups, with more than half of the treated mice surviving beyond 60 days. This combination strategy enhanced E7-specific CD8⁺ T cell immunity in peripheral blood and the spleen, reduced myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, promoted splenic T cell memory formation, and reshaped the tumor microenvironment. Conclusions: Combining vaccine SOMV-9RE7 with alb-Flt3L improves antitumor efficacy and durability. This therapeutic benefit is associated with both systemic and local immune remodeling, supporting the combination therapy as a promising strategy for therapeutic cancer vaccines. Full article

Prostate cancer remains a major clinical challenge, partly due to tumour–immune interactions that contribute to immune evasion and therapeutic resistance. The CD47–SIRPα axis is a key macrophage-associated immune recognition pathway; and materials-oriented platforms that allow preliminary investigation of tumour–macrophage interaction patterns remain valuable. Here, we report an optically traceable biohybrid nanoplatform based on CD47 aptamer-functionalized fluorescent carboxyl-functional MMES-POSS hybrid nanoparticles. The nanoparticles were synthesized within 5 min using UV-induced free-radical emulsion polymerization in an ethanol–water system and exhibited spherical morphology, SEM-derived dry-state mean diameters below 100 nm, negative surface charge, and retained fluorescence due to RITC encapsulation within the crosslinked hybrid matrix; however, DLS measurements revealed pronounced aggregation and polydispersity in aqueous dispersion. SEM and EDX provided complementary evidence of nanoparticle morphology and elemental composition, whereas zeta potential and Nanodrop measurements provided evidence consistent with surface functionalization, and FTIR confirmed retention of the core POSS, carbonyl, and RITC-associated chemistry. In a PC-3/THP-1 macrophage co-culture model, Annexin V–FITC/PI flow cytometry showed a concentration-dependent redistribution of cell populations, with the most pronounced early apoptotic enrichment observed at 2 µg/mL. However, pairwise exploratory comparisons among concentrations did not reach statistical significance, and this is discussed as a limitation of the present exploratory dose–response characterization. These findings indicate preliminary interaction-associated response patterns rather than definitive receptor-specific targeting or therapeutic CD47–SIRPα blockade. Overall, this modular POSS-based biohybrid interface provides a materials-oriented platform for probing prostate cancer–macrophage interaction profiles and guiding future mechanistic validation studies. Full article

Triple-negative breast cancer (TNBC) is associated with recurrence, metastasis, and limited durable responses to immunotherapy, in part due to persistence of breast cancer stem cells (BCSCs). We investigated whether CD6-directed immunotherapy with the monoclonal antibody UMCD6 enhances immune-mediated killing and alters function of BCSC in stem cell-enriched TNBC models. The SUM-149 and SUM-159 cell lines were analyzed for CD6 ligand expression, cocultured with human peripheral blood mononuclear cells (PBMCs) treated with UMCD6, pembrolizumab, or isotype control, and assessed by live-cell cytotoxicity imaging, flow cytometry, soft agar colony formation, and extreme limiting dilution sphere assays. Both TNBC lines co-expressed the CD6 ligands CD44, CD166/ALCAM, and CD318/CDCP1. UMCD6 significantly increased PBMC-mediated apoptosis and reduced tumor cell survival in both models, with greater activity than pembrolizumab under these in vitro conditions. In surviving SUM-159 cells, UMCD6 reduced the ALDH⁺ population wit×hout significantly altering CD44⁺CD24⁻ frequency, indicating preferential effects on a distinct stem-like compartment. Functionally, UMCD6 decreased anchorage-independent colony formation and reduced sphere-forming frequency from 1/33.6 to 1/68.3 cells (p = 0.0186). These findings identify the CD6 ligand axis as a therapeutic vulnerability in BCSC-enriched TNBC and support further preclinical evaluation of CD6-directed immunotherapy as a strategy to enhance antitumor immunity while limiting tumor-initiating capacity. Full article

Background/Objectives: High linear energy transfer (LET) carbon ions achieved more effective and biologically robust tumor control than photons in preclinical prostate cancer models; however, the longitudinal development of histopathological parameters remains insufficiently characterized, limiting the selection of the optimal treatment modality in patients. This study analyzed the temporal histological patterns after isoeffective photon, proton, and carbon ion irradiations. Methods: Two Dunning R3327 prostate carcinoma sublines (H, HI) grown subcutaneously in male Copenhagen rats received single-fraction isoeffective curative photon or carbon ion doses. For HI-tumors, the effectiveness of isoeffective curative proton doses and isoeffective subcurative photon and carbon ion doses was additionally investigated. Tumors were collected prior and up to 3 weeks after irradiation and processed for quantitative histology of proliferation (BrdU), DNA damage (γH2AX), hypoxia (pimonidazole), vascular (CD31), and immune cell (CD3, CD68) markers. Results: All modalities induced an early peak in γH2AX⁺ tumor cells and a pronounced suppression of BrdU⁺ cells, with more sustained effects after isoeffective carbon ions doses, particularly in the HI-tumors. These findings, however, differed strongly between hypoxic and oxic micro-environments. Vascular parameters, diffusion distances, and global and compartment-specific hypoxic fractions showed distinct temporal dynamics between photons and carbon ions in HI-tumors, whereas H-tumors exhibited more moderate and reversible changes. At curative carbon ion doses, there was a late rebound of BrdU-positive tumor cells and increased CD68⁺ macrophage accumulation in chronically hypoxic regions. CD3⁺ T cells showed a biphasic decrease-recovery pattern in HI-tumors largely independent of radiation quality and oxygenation. Conclusions: Longitudinal histology revealed modality- and tumor-line-specific trajectories of tumor, vascular, hypoxic, and immune responses after isoeffective photon, proton, and carbon ion irradiations in prostate carcinoma. The more persistent tumor cell damage and distinct vascular response, together with late proliferative and macrophage rebounds under chronic hypoxia after carbon ions, provide mechanistic support for the increased biological effectiveness and highlight hypoxia-driven repopulation and inflammation as key processes. Full article