Retinoblastoma (RB) represents the most common primary intraocular malignancy in childhood and stands as a paradigm for translating molecular oncology into precision clinical management. This review synthesizes the comprehensive evolution in the understanding and treatment of RB. First, we deconstruct the intricate oncogenic circuitry that extends far beyond Knudson's classic "two-hit" RB1 inactivation model, describing non-classical MYCN-driven pathogenesis, multi-layered epigenetic reprogramming (including chromatin, RNA and histone changes), and distinct histological subtypes with defined clinical correlates, such as the favorable-prognosis cavitary RB. Single-cell genomics has elucidated the cellular origin from cone precursor cells and intratumoral heterogeneity. Risk stratification has been refined through well-defined classification systems, from the therapy-guiding International Intraocular Retinoblastoma Classification (IIRC) to the comprehensive American Joint Committee on Cancer Tumor-Node-metastasis (AJCC TNM) staging. Furthermore, the diagnostic paradigm has advanced from conventional anatomical imaging to liquid biopsies, enabling non-invasive molecular staging and monitoring via tumor-derived cell-free DNA analysis. Concurrently, the therapeutic landscape has undergone a radical shift, moving from enucleation and external-beam radiotherapy to an era dominated by local sight-preserving strategies. We provide a critical synthesis of the evidence for intravenous chemotherapy and the transformative role of super-selective intra-arterial chemotherapy (IAC), and describe essential randomized controlled trials, technical innovations, and optimized drug regimens. Finally, we explore emerging targeted molecular therapies and future directions. By integrating cutting-edge molecular insights with robust, high-level clinical evidence, this review offers the framework for achieving patient and eye survival as well as vision preservation in children with Retinoblastoma.

Lactate was once regarded merely as a byproduct of glycolysis, but is now recognized as a multifunctional metabolite that coordinates energy redistribution, intercellular communication, receptor-mediated signaling, and epigenetic regulation. In the retina, these functions are especially consequential because visual processing depends on a highly specialized and energetically demanding tissue, characterized by steep oxygen gradients, a dual vascular supply, and tightly integrated metabolic crosstalk among photoreceptors (PCs), Müller glia, the retinal pigment epithelium, vascular cells, and retinal ganglion cells. In this review, we synthesize current advances in lactate signaling and lactylation in the retina, and examine how their dysregulation contributes to neovascularization, inflammation, and neurodegeneration in disorders including diabetic retinopathy, age-related macular degeneration, autoimmune uveitis and glaucoma. Drawing from these metabolic insights, therapeutic interventions targeting lactate signaling and lactylation are discussed as potential approaches to mitigate retinal abnormalities. Collectively, this review highlights the central importance of lactate signaling and lactylation in retinal physiology and pathology, and provides a conceptual framework for developing metabolic interventions aimed at restoring retinal lactate homeostasis.

MYCN amplification is a recurrent, high-risk molecular hallmark across diverse tumors, most notably neuroectodermal malignancies. Although MYCN-driven tumors uniformly exhibit robust intrinsic resistance to ferroptosis, the mechanistic link between MYCN and the ferroptotic pathway remains undefined. Here, we charted the genomic and epigenomic landscape of neuroectodermal tumors by combining single-cell RNA-seq, spatial transcriptomics (ST), CUT&Tag, and deep-coverage mass spectrometry proteomics. This integrative atlas identified UBE2C as a spatially resolved, MYCN-controlled driver gene. MYCN occupies the UBE2C promoter and potently transactivates its transcription, thereby accelerating tumor progression in vitro and in vivo. Re-expression of UBE2C fully rescued the proliferative arrest triggered by MYCN depletion, confirming its essential function downstream of MYCN. Proteomic interrogation of the UBE2C interactome further revealed that the tumor suppressor TFRC is a previously unknown ubiquitination substrate of UBE2C. Mechanistically, the polyubiquitination and proteasomal degradation of TFRC by UBE2C reduces iron influx and effectively shields cancer cells from ferroptosis. Clinically, genetic silencing of UBE2C induces ferroptosis and sensitizes tumor cells to the ferroptosis inducer erastin, revealing a therapeutically exploitable vulnerability in MYCN-amplified malignancies. Our study reveals a previously unrecognized MYCN-UBE2C-TFRC-ferroptosis regulatory axis that drives neuroectodermal tumor growth. These findings establish a mechanistic rationale for combining UBE2C silencing and ferroptosis induction as a precision therapeutic strategy against MYCN-amplified tumors.

Radiotherapy (RT) stands as one of the most widely used and effective modalities in the clinical treatment of malignant tumors. A key advancement in modern precision RT technology is to improve therapeutic gain ratios through physical techniques. However, RT efficacy remains constrained by multiple factors, including the low sensitivity of tumor tissue to RT, the dose-limiting constraints of RT, and the intrinsic capacity of tumors to repair radiation-induced damage. Thus, enhancing the sensitivity of tumor cells to RT has become a current research focus. The sensitivity of malignant tumors to RT is governed primarily by multiple factors, including the intratumoral oxygen levels, specific redox states, distinct tumor cell cycle phases, and the inherent physiological barriers imposed by the tumor microenvironment (TME). In recent years, bionanomaterials have garnered substantial attention in biomedical research due to their unique physicochemical properties and functional versatility. Their application as radiosensitizers to augment tumor tissue responsiveness to RT has rapidly evolved into a prominent research frontier. In this review, we first elucidate the fundamentals of RT and bionanomaterials, followed by a comprehensive analysis of nanomaterial-based radiosensitization strategies tailored to address distinct influencing factors. We further outline emerging synergistic approaches that combine nanomaterials with RT to induce regulated tumor cell death (RCD) and summarize the relevant clinical research on the use of nanomaterials as radiosensitizers, aiming to highlight the research progress in nanomaterial-enabled RT enhancement. Finally, the challenges and opportunities for bionanomaterials as radiosensitizers are discussed further, providing actionable insights for translational research.

PURPOSE. Uveal melanoma (UM), the most prevalent primary intraocular cancer in adults, is defined by salient histopathological diversity. Spindle and epithelioid cells constitute its two dominant pathological lineages, yet the latter foreshadows aggressive behavior and shortened survival. This study aimed to explore the molecular and metabolic underpinnings of UM pathology using regionally resolved proteomics. METHODS. Formalin-fixed, paraffin-embedded tumors from four patients-two spindle cell and two epithelioid-were histologically stratified via hematoxylin and eosin staining and subsequently interrogated by regionally resolved proteomics across eight precisely mapped regions. Immunofluorescence corroborated the shifts in melanocyte lineage markers. To translate these tissue-level signatures into functional biology, spindle-like 92.1 and epithelioid Mel290 cell lines were subjected to quantitative RT-PCR and Seahorse metabolic profiling, quantifying oxidative-phosphorylation (OXPHOS) gene expression and mitochondrial respiration. RESULTS. Proteomic profiling of microdissected tissue uncovered a selective collapse of the melanocytic differentiation program within epithelioid foci. Endothelin receptor type B, the receptor required for melanocyte stem cell fate, and the lineage-defining calciumbinding protein S100B were both sharply repressed in epithelioid samples, with S100B registering the single largest drop across the entire dataset. Immunofluorescence corroborated this signature, revealing concomitant loss of microphthalmia-associated transcription factor and premelanosome protein, further attesting to the dedifferentiated state of epithelioid cells. Simultaneously, the same regions exhibited a striking surge in OXPHOS machinery. Concordantly, Mel290 epithelioid cells displayed elevated transcription of OXPHOS genes and a markedly higher basal and maximal oxygen consumption rate compared with the spindle-like 92.1 line, aligning tissue-level proteomic shifts with cellautonomous metabolic rewiring. CONCLUSIONS. Our findings reveal a distinct proteomic signature in epithelioid UM characterized by dedifferentiation and enhanced mitochondrial respiration. This study provides the first regionally resolved proteomic landscape of UM pathology and suggests that the epithelioid transformation may reflect a shift toward a dedifferentiated, metabolically active tumor state.

Chemoresistance remains a significant challenge in cancer treatment, substantially limiting therapeutic efficacy. Cuproptosis is copper-induced cell death driven by mitochondrial protein aggregation and metabolic dysfunction. However, the involvement of cuproptosis in chemoresistance remains enigmatic. This study reveals that epigenetic remodeling augments mitochondrial respiration, thereby sensitizing cells to elesclomol-induced cuproptosis in cisplatin-resistant uveal melanoma (UM). First, we established cisplatin-resistant UM cell lines, which were validated in vitro and in vivo. A multi-omics analysis, including transcriptomics, metabolomics, and histone acetylation profiling (H3K9Ac/H3K27Ac CUT&Tag), revealed an upregulation of mitochondrial respiration and downregulation of glycolysis in cisplatin-resistant cells due to changes in histone acetylation. This metabolic reprogramming was associated with increased sensitivity to elesclomol-mediated cuproptosis, characterized by the diminishment of Fe–S cluster proteins and DLAT aggregation. Our research further delineated that the absence of FDX1 not only mitigated the sensitivity of chemoresistant UM cells to elesclomol but also attenuated copper-induced cell death, thereby substantiating the pivotal role of cuproptosis in this context. Therapeutically, employing zebrafish models, orthotopic xenografts, and patient-derived xenografts (PDXs), we confirmed the therapeutic efficacy of elesclomol in overcoming chemoresistance. Collectively, our study highlights a novel avenue for the development of a combinatorial therapeutic approach employing cisplatin and elesclomol to improve chemotherapy outcomes.

The disruption of vascular homeostasis is a key pathological feature of fundus abnormal vascular diseases, including wet age-related macular degeneration, diabetic macular edema, and retinal vein occlusion. While anti-vascular endothelial growth factor therapies are widely used, many patients exhibit limited or suboptimal responses. Through proteomic analysis of 173 aqueous humor samples from fundus abnormal vascular disease patients, followed by validation in an independent cohort of 70 samples, this study identifies prosaposin as a potential therapeutic candidate. In vitro, prosaposin mitigated endothelial dysfunction and reduced vascular permeability, while in vivo, it demonstrated anti-angiogenic and anti-inflammatory effects comparable to aflibercept, effectively reducing vascular leakage and retinal edema. Additionally, prosaposin provided neuroprotection by preserving photoreceptor cells. These findings highlight the dual role of prosaposin in maintaining vascular homeostasis and protecting neural tissues, suggesting its potential as an alternative treatment for patients unresponsive to anti-vascular endothelial growth factor therapies.

PURPOSE:To evaluate the safety and effectiveness of eye-preserving therapies in patients with American Joint Committee on Cancer (AJCC) eighth edition cT3c retinoblastoma presenting with neovascular glaucoma (NVG) without buphthalmos (defined as early cT3c), focusing on overall survival and eye preservation. DESIGN:Retrospective, single-center cohort study. PARTICIPANTS:132 patients diagnosed with early cT3c retinoblastoma from May 2014 through October 2024. METHODS:The patients were divided into primary enucleation (50 patients) and primary eye-preserving groups (82 patients). They were followed up for survival status and ocular outcomes. MAIN OUTCOMES MEASURES:Overall survival, high-risk pathological features, globe salvage and vision preservation. RESULTS:After a median follow-up of 52.9 months, one death occurred in each group, and overall survival did not differ significantly between the primary eye-preserving and primary enucleation groups (log-rank test, P = 0.775). Eye-preserving therapies were associated with a lower incidence of high-risk pathological features (odds ratio [OR], 0.21; P = 0.003), with attenuated severity of both choroidal (OR, 0.25; P = 0.002) and optic nerve invasion (OR, 0.23; P = 0.008). The globe salvage rate was 49.4% (41/83) in the primary eye-preserving group. And among these preserved eyes, 46.3% (19/41) regained light projection or better after receiving eye-preserving therapies. Importantly, presenting intraocular pressure (IOP) ≥32 mmHg (hazard ratio [HR], 2.37; P = 0.010) and corneal edema (HR, 2.86; P = 0.007) were high risk factors for globe salvage failure. Compared with intravenous chemotherapy (IVC) alone, application of intra-arterial chemotherapy (IAC; HR, 0.13; P = 0.001) alone and combined IVC-IAC regimens (HR, 0.15; P = 0.001) demonstrated a significantly association with better globe salvage outcomes. Additionally, cryotherapy (HR, 0.14; P < 0.001) was identified as an independent protective factor for overall globe salvage. CONCLUSION:Primary eye-preserving therapies can secure high rates of globe salvage with partial visual function in patients with early cT3c retinoblastoma, without jeopardizing patient survival. However, eyes exhibiting corneal edema or IOP ≥32 mmHg demonstrate markedly inferior salvage outcomes, the treatment strategy for such patients must therefore be cautiously individualized.

Uveal melanoma (UM) is a rare yet aggressive malignancy with a high propensity for distant metastasis and poor response to systemic therapies, including immunotherapies. Although recent single-cell studies have uncovered pronounced intratumoral heterogeneity and an immunosuppressive tumor microenvironment, the tumor-intrinsic metabolic programs that drive immune escape remain poorly defined. Here, we performed single-cell RNA sequencing on primary UM specimens to generate a high-resolution atlas of tumor and immune cell states. We identified a redox-optimized melanoma subpopulation under heavy metabolic-proteostatic demand, characterized by intensive protein secretory activity and elevated antioxidant defenses. This adaptive state is required to sustain the robust secretion of the matricellular protein SPP1, which suppressed the proliferation and function of CD8+ T cells through CD44 engagement. Disruption of redox equilibrium by enhancing reactive oxygen species (ROS) via a mitochondria-targeted oxidative phosphorylation inhibitor triggered endoplasmic reticulum stress and downregulated SPP1 expression, thereby defining a direct metabolic-immune regulatory axis. Together, our findings reveal a previously unrecognized ROS-SPP1-CD44 axis that links tumor redox homeostasis to immune evasion, providing mechanistic insight into the immune-resistant phenotype of UM and suggesting potential therapeutic vulnerabilities within the metabolic-immune crosstalk.

AIMS:To evaluate survival, globe salvage and visual outcomes of globe-preserving treatment approaches in unilateral cT2 and cT3 retinoblastoma, with a focus on cT3 disease. METHODS:This multicentre, retrospective cohort study enrolled 1566 treatment-naïve unilateral retinoblastoma eyes (870 clinical (c)T2, 696 cT3 by eighth American Joint Committee on Cancer clinical tumour, node, metastases staging) from 11 Chinese tertiary centres. Patients underwent intra-arterial chemotherapy, intravenous chemotherapy or primary enucleation. Outcomes were globe salvage, overall survival, metastasis-free survival, high-risk histopathological feature prevalence and vision-preserving rate (≥light perception (LP)). RESULTS:In this multicentre cohort of 1566 eyes, the globe-salvage rate across cT2 and cT3 retinoblastoma was higher with intra-arterial chemotherapy than with intravenous chemotherapy. When stratified by cT3 subcategories, intra-arterial chemotherapy achieved significantly higher globe-salvage rates than intravenous chemotherapy in cT3b eyes (HR 3.65; 95% CI 1.91 to 6.98) and cT3c eyes (HR 4.02; 95% CI 2.79 to 5.80). In contrast, globe salvage did not differ between intra-arterial chemotherapy and intravenous chemotherapy in cT3d eyes. Overall survival and metastasis-free survival did not differ between intra-arterial chemotherapy and primary enucleation. Among eyes with cT3b or cT3c disease, 79.4% of eyes salvaged with intra-arterial chemotherapy and 65.0% of eyes salvaged with intravenous chemotherapy retained at least LP. Detected high-risk pathological features were not significantly different between eyes treated with intra-arterial chemotherapy and those undergoing primary enucleation in cT3b or cT3c disease. Among secondary enucleated eyes with cT3d disease, intra-arterial chemotherapy was associated with lower rates of choroidal invasion. CONCLUSION:Intra-arterial chemotherapy may enable globe salvage in cT3b/c retinoblastoma, whereas cT3d eyes continue to warrant prompt enucleation.

Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.

Histidine phosphorylation, the neglected but vital phosphoproteome, is a reversible posttranslational modification catalyzed by histidine kinases and erased by phosphohistidine (pHis) phosphatases (e.g., LHPP). Traditional types of phosphorylation have been implicated with the deadliest adult ocular tumor uveal melanoma (UM), which is lipid metabolism dysfunction related. However, the role of histidine phosphorylation in UM remains unknown. Here, up-regulated histidine phosphorylation is associated with poor UM prognosis. Reversal of histidine phosphorylation by LHPP exerts therapeutic effects. Mechanistically, we identified LHPP as metabolically related protein with mitochondrial targeting sequence. LHPP interacts and reduces excessive histidine phosphorylation of mitochondrial aconitase ACO2 at H73 site, thus restoring ACO2 enzymatic activity and mitochondrial citrate transit in TCA cycle. Reduction of citrate accumulation attenuates overloaded lipid synthesis. Besides, genetic ablation of LHPP in mouse eye exhibits abnormal lipid metabolism. These findings illustrate the antagonistic roles of oncogenic histidine phosphorylation and therapeutic mitochondrial LHPP and provide metabolic insight of pHis modification in ocular diseases.

The next-generation gene editing tool, prime editing (PE), is adept at correcting point mutations precisely with high editing efficiency and rare off-target events and shows promising therapeutic value in treating hereditary diseases. Retinitis pigmentosa (RP) is the most common type of inherited retinal dystrophy and is characterized by progressive degeneration of retinal photoreceptors and, consequently, visual decline. To date, effective treatments for RP are lacking. Herein, a PE system is designed to target the PDE6B Y347X mutation in the rd1 mouse strain, a preclinical RP model. We screen and develop the PE system with epegRNA and RTΔRnH, which is delivered via dual-AAV in vivo with an editing efficiency of 26.47 ± 13.35%, with negligible off-target effects confirmed by AID-Seq and PE-tag. Treatment with the PE system in vivo greatly restores PDE6B protein expression and protects rod cells from degeneration. Mouse behavioural experiments also show that compared with no treatment, prime editing inhibits vision deterioration in littermate rd1 mice. This study provides a therapeutic opportunity for the use of PE to correct mutated RPs at the genomic level. Retinitis pigmentosa (RP) is the most common type of inherited retinal dystrophy without effective treatments. Here, authors apply prime editing (PE) system to correct the point mutation in a preclinical RP mouse model. In vivo treatment achieves genome editing and restores mice vision.

Behçet's uveitis (BU), characterized by recurrent bilateral panuveitis, is a severe manifestation of Behcet's disease (BD). However, disease-specific metabolic alterations in BU remain largely unknown. Here, untargeted metabolomics and single-cell RNA sequencing (scRNA-seq) are performed in patients with BU and healthy controls (HC). scRNA-seq data of experimental autoimmune uveitis (EAU) mice are also incorporated. The data showed an altered metabolic profile, characterized by upregulated glycolysis in BU. MYC is predicted to be a hub molecule regulating glycolysis and T cell response. Notably, it is discovered that the expression level of MYC is higher in BU compare to HC and may reflect the treatment response of BU disease. Correspondingly, the scRNA-seq data of EAU mice also reveal higher glycolysis levels and MYC expression. Further studies reveal that inhibition of MYC repressed glycolysis and exerted therapeutic effects similar to those of glycolysis inhibitors, including amelioration of EAU and repression of the abnormal response of effector T cells (T helper [Th]-1 and Th17 cells). Mechanically, inhibiting MYC disrupts the glycolysis-PI3K signaling circuit to curb the effector T cell response in uveitis. Collectively, the study indicated that MYC promoted glycolysis to fuel abnormal T-cell responses, thus therapeutically targeting MYC would provide an attractive approach for treating BU.

Cancer metabolic reprogramming is a fundamental hallmark that enables tumor cells to sustain their malignant behaviors. Beyond its role in supporting growth, invasion, and migration, metabolic rewiring actively contributes to anticancer drug resistance. Cancer cells not only reshape their own metabolism but also engage in aberrant metabolic crosstalk with nonmalignant components within the tumor microenvironment (TME). These metabolic alterations create multiple barriers to the efficacy of drug therapies, including chemotherapy, targeted therapy, and immunotherapy. Despite growing evidence, an integrated understanding of how metabolic reprogramming contributes to the development of drug resistance and how it may be therapeutically targeted to overcome the resistance remains incomplete. This review summarizes recent progresses in tumor-intrinsic and TME-associated metabolic alterations that contribute to drug resistance by sustaining metabolic needs and modulating nonmetabolic processes and explores the upstream regulatory mechanisms driving these changes, focusing particularly on glucose, lipid, and amino acid metabolism. We also discuss the current advances in the integration of small molecule inhibitors targeting cancer metabolism to address drug resistance. By consolidating mechanistic insights and therapeutic opportunities, this review highlights metabolic reprogramming as a promising intervention point to overcome anticancer drug resistance.

Autoimmune toxicity affects up to 60 % of patients receiving immune checkpoint inhibitor (ICI) therapy for cancer, presenting a notable clinical obstacle that constrains its wider application. Hence, there is an imperative demand to develop novel strategies to manage immune-related adverse events (irAEs). Ifosfamide (IFO) shares structural and functional resemblances with cyclophosphamide (CPA). Despite the acknowledged dual anti-tumor and immunomodulatory effects of CPA, the specific effect of IFO on autoimmune conditions remains elusive. Here, we evaluated the efficacy of IFO on experimental autoimmune uveitis (EAU) mouse models and explored the cell-specific effects of IFO under autoimmune conditions using single-cell RNA sequencing. Our data indicated that IFO effectively alleviated inflammatory infiltration and reversed pathological alterations of EAU. Subsequent single-cell data analysis and in vivo experiments suggested IFO exerted broad suppressive effects on autoimmune responses, concurrently restoring the balance between Th17 and Treg populations. In addition, we observed that IFO enhanced CD8+ T cell activation and its cytotoxic immune responses, highlighting the cell-type-specific immunomodulatory effects of IFO. Moreover, we constructed EAU models on tumor-bearing mice under ICI treatment, and found that ICI exacerbated EAU symptoms. IFO not only possessed anti-tumor effects as monotherapy, but also augmented ICI efficacy by promoting CD8+ T cell-mediated immunity. Furthermore, we found that IFO alleviated EAU symptoms exacerbated by ICI treatment and effectively restored Th17/Treg balance. Our results elucidated the immunomodulatory effects of IFO treatment, providing evidence for the application of IFO in managing autoimmune conditions and irAEs.

The role of innervation in the pathogenesis of malignancies has been documented in many investigations. Recent studies have revealed that neurotransmitters act as mediators in nerve-stimulated cancer progression by directly influencing tumor cells and modulating the tumor microenvironment, including immune cells, angiogenesis, and surrounding stromal cells. Notably, psychological stress has been identified as a contributing factor to oncogenesis, primarily mediated by neurotransmitters. However, the complex interplay between neurotransmitters and tumor cells remains only partially understood. In this review, we explore newly identified mechanisms through which neurotransmitters (acetylcholine, glutamate, serotonin, dopamine, adrenaline, noradrenaline, γ-aminobutyric acid, neurotensin, and neuropeptide Y) regulate cancer initiation and progression, along with potential therapeutic strategies derived from these findings.

Eliciting ferroptotic cell death in tumors has enhanced prospects for cancer therapy because of its proinflammatory properties, which enable damage-associated molecular pattern (DAMP) release and immune response activation. However, the immunogenicity of ferroptosis and how to controllably activate the self-enhanced antitumor immune response by cellular ferroptosis require further investigation. In this study, a piezoelectric BaTiO3-based ferroptosis inducer (BTO@Fe) is synthesized for effective cancer immunotherapy. BTO@Fe induces moderate ferroptosis by introducing excess iron and catalyzing the Fenton reaction. When subjected to ultrasound (US) irradiation, the piezoelectrically excited electrons and holes are separated, further catalyzing reactive oxygen species (ROS) generation and glutathione (GSH) consumption and consequently causing intensified ferroptosis and immunogenic cell death (ICD). Moreover, activated CD8+ T cells respond to immune signals by releasing interferon gamma (IFNγ), which sensitizes tumor cells to ferroptosis in an intrinsic mechanism of ferroptosis initiation. The robust ferroptosis originating from exogenous piezocatalytic reactions and the endogenous immune responses demonstrates satisfactory in vitro and in vivo antitumor effects. This work suggests that doping-engineered piezoelectric materials with augmented catalytic activity are promising countermeasures for restoring immunogenicity in ferroptotic cells.

The activity of neurons in the vicinity of tumors is linked to a spectrum of cellular mechanisms, including the facilitation of tumor cell proliferation, synapse formation, angiogenesis, and macrophage polarization. This review consolidates the current understanding of neuro-oncological regulation, underscoring the nuanced interplay between neurological and oncological processes (termed as Cancer-Neuroscience). First, we elucidated how the nervous system accelerates tumor growth, metastasis, and the tumor microenvironment both directly and indirectly through the action of signaling molecules. Importantly, neural activity is also implicated in modulating the efficacy of therapeutic interventions, including immunotherapy. On the contrary, the nervous system potentially has a suppressive effect on tumorigenesis, further underscoring a dual-edged role of neurons in cancer progression. Consequently, targeting specific signaling molecules within neuro-oncological regulatory pathways could potentially suppress tumor development. Future research is poised to explore the intricate mechanisms governing neuro-tumor interactions more deeply, while concurrently refining treatment strategies for tumors by targeting the crosstalk between cancer and neurons.