搜索结果：Translational oncology

IDH305 was developed as an orally available, mutant-selective, allosteric inhibitor of isocitrate dehydrogenase (IDH)1 for cancer treatment. It is a substrate, time-dependent inhibitor, and inducer of cytochrome P450 (CYP)3A4. As part of model-informed drug development (MIDD) of IDH305, two prospective physiologically based pharmacokinetic (PBPK) models were developed and CYP3A4 humanized mouse model was utilized to inform the first-in-human (FIH) study, where patients with advanced malignancies were to take IDH305 twice daily. The objectives are addressing whether food could be given with IDH305 and whether accumulation or reduction of PK exposure would occur follow repeat dosing. The absorption PBPK model predicted no food effect of light meals at 300 mg dose and informed the FIH study to allow dosing with light meals in cancer patients. The metabolic PBPK model, along with CYP3A4 humanized mouse studies, evaluated the interplay of CYP3A4 inhibition and induction and predicted a net outcome of modest accumulation (accumulation ratio 1.5-1.9). Both the predicted food effect and accumulation ratio were consistent with the observed data in the FIH study. This integrative translational approach informed clinical development of IDH305 and can be used to support MIDD of molecules with complex metabolic properties in oncology drug development.

Cancer remains a leading cause of mortality worldwide, highlighting the need for therapeutic strategies that reduce systemic toxicity and drug resistance. Resveratrol (RES), a natural polyphenolic stilbenoid, possesses antioxidant, anti-inflammatory, pro-apoptotic, anti-metastatic, and chemosensitizing activities. However, its clinical translation is limited by poor aqueous solubility, chemical instability, rapid metabolic clearance, and consequently low systemic bioavailability. Nanotechnology-based drug delivery systems provide a promising strategy to address these limitations. This review summarizes recent advances in RES-loaded nanoformulations, including polymeric nanoparticles, liposomes, solid lipid nanoparticles, micelles, inorganic nanocarriers, protein-based systems, and biomimetic vesicles. Their therapeutic performance is evaluated across prostate, lung, colorectal, breast, and other cancers, with attention to tumor targeting, controlled release, combination therapy, multidrug-resistance reversal, and modulation of cancer-relevant pathways such as NF-κB, p53, and PI3K/Akt/mTOR. Current oncology-related clinical evidence for RES is still largely based on conventional oral or micronized formulations. Translation of engineered RES nanocarriers therefore requires stronger evidence on scalable manufacturing, carrier-specific safety, heterogeneous tumor delivery, and biomarker-guided trial design. This review also introduces a semi-quantitative prioritization framework based on model-readiness, translational priority, and safety-alert scoring for future PBPK, PK-PD, nano-QSAR, and machine-learning analyses.

Quorum sensing (QS) orchestrates virulence, biofilm maturation, and antimicrobial tolerance across clinically dominant pathogens, driving chronic infections and therapeutic failure. Although quorum-sensing inhibitors (QSIs) were developed to attenuate pathogenic coordination without bactericidal pressure, their clinical translation has been constrained by biochemical instability, narrow receptor specificity, limited pharmacokinetic robustness, and emerging adaptive resistance. Molecularly imprinted polymers (MIPs) provide a mechanistically distinct strategy based on structurally defined recognition cavities capable of physically sequestering or catalytically degrading autoinducers with measurable thermodynamic parameters, including the imprinting factor (IF), dissociation constant (K d), and binding capacity. This review critically synthesizes advances in molecularly imprinted polymer design for QS detection and modulation, emphasizing the role of monomer-template complementarity, cross-link density, porogen environment, polymerization strategy, and template removal in governing recognition fidelity and biological performance. Computational modeling has improved monomer selection and prepolymerization complex prediction, yet translational reliability requires integration of solvent dynamics, cross-linker effects, and matrix competition under physiologically relevant conditions. Compared with conventional biosensors and small-molecule QSIs, MIPs demonstrate nanomolar detection limits, resilience in complex media, and up to 80% biofilm inhibition through signal sequestration. Early in vivo studies further support their potential to attenuate the QS-dependent virulence. Despite these advances, barriers remain, including monomer cytotoxicity, nonspecific adsorption in biological fluids, incomplete biodegradation profiling, and the need for standardized in vivo validation frameworks. With rational engineering and regulatory alignment, MIPs represent a programmable materials platform for communication-based infection control, expanding the antivirulence paradigm beyond receptor antagonism toward structurally resilient quorum interception.

Leukemia predominantly affects the elderly, who face unique clinical challenges related to aging physiology, comorbidities, and social determinants of health. These challenges are further exacerbated in underserved regions where diagnostic and treatment resources are scarce, resulting in delayed diagnoses, limited access to effective therapies, and poorer survival outcomes. This review explores the multifaceted barriers to equitable leukemia care for elderly patients in resource-limited settings, emphasizing the urgent need for targeted interventions. Recent therapeutic advances, including hypomethylating agents, targeted oral therapies, and reduced-intensity conditioning regimens, have improved survival and quality of life for older leukemia patients in high-income settings. However, their availability and implementation in underserved regions remain inadequate due to economic, infrastructural, and policy constraints. We discuss emerging strategies such as decentralizing diagnostics, integrating comprehensive geriatric assessments, leveraging telemedicine, and fostering inclusive clinical trials that can help bridge these gaps. Addressing disparities in geriatric leukemia care demands a coordinated approach involving healthcare providers, policymakers, and community stakeholders. By expanding access to diagnostics and novel therapies, strengthening supportive care, and prioritizing research in diverse populations, the global oncology community can move towards equitable care delivery. Ultimately, ensuring that elderly leukemia patients in underserved regions receive personalized, evidence-based treatment is critical to improving outcomes and honoring their dignity.

To evaluate whether [68Ga]Ga-FAPI-46 PET/CT (FAPI PET) is sensitive to neoadjuvant chemotherapy (NAC)-associated changes in peritoneal carcinomatosis (PC) and whether post-NAC FAPI PET parameters and pre-/post-NAC changes are associated with histopathologic and biochemical response. This exploratory translational sub-cohort analysis was conducted within the prospective phase II FAPeCa trial (NCT06061874) recruiting patients with colorectal or ovarian cancer with known/suspected PC. Patients who received recent chemotherapy were included in the current analysis. PET parameters, including SUVmax, peritoneal tumour volume (PTV), and total lesion uptake (TLF/TLG) were analysed both on FAPI and [18F]-FDG PET/CT. Associations with pathological chemotherapy response score (pCRS) and CA-125 change were explored. Pre- and post-NAC paired FAPI PET and FAP immunohistochemical (IHC) analyses were performed. Segment-level correlation between IHC score and FAPI PET uptake was assessed. Twenty-seven patients were included, predominantly with ovarian cancer (26/27), including 10 with paired pre-/post-NAC imaging. All paired FAPI PET parameters declined significantly after NAC. The magnitude of change in paired FAPI PET parameters correlated strongly with pCRS, particularly for SUVmax (ρ=0.866, p=0.005), PTV(2.5) (ρ=0.830, p=0.011), and TLF(2.5) (ρ=0.830, p=0.011), whereas FDG PET parameters and FAPI PTV(40) and TLF(40) showed no significant correlation with pCRS. Changes in FAPI PET parameters also correlated with the CA-125 change. Across the post-NAC cohort, FAPI PET volumetric parameters differed significantly across pCRS categories. Paired IHC demonstrated a significant reduction in FAP expression after NAC, and segment-level FAP IHC score showed a significant moderate correlation with FAPI uptake (SUVmax ρ=0.467, p=0.012; SUVmean ρ=0.554, p=0.005). [68Ga]Ga-FAPI-46 PET/CT demonstrated treatment sensitivity after NAC in PC, with concordant reductions in PET parameters and stromal FAP expression. FAPI PET volumetric parameters were associated with histopathologic response and CA-125 change in this exploratory sub-cohort, supporting further investigation of FAPI PET as an imaging biomarker for response assessment in PC.

Sirtuins (SIRT1-SIRT7) are a family of NAD+-dependent lysine deacetylases that possess mono-ADP-ribosyltransferase activity and integrate cellular metabolic status with chromatin regulation, genome maintenance, redox homeostasis, immune responses, and adaptation to cancer therapies. Their translational value has been obscured by a recurring paradox: the same isoform may constrain malignant transformation in one setting yet support metastatic competence, stemness, immune evasion, or drug resistance in another. This review reframes that paradox as a measurable problem of context. We define a SIRT context code in which NAD+ availability and compartmentalization, subcellular localization, PTM state, chromatin occupancy, oncogenic genotype, cell lineage, and tumor microenvironment jointly determine sirtuin output. Using recent mechanistic and translational evidence, we summarize how sirtuins regulate metabolic switching, histone acetylation and lactylation, genome stability, cancer-associated fibroblast programs, regulatory T-cell enrichment, cancer stem-cell plasticity, angiogenesis, and resistance to DNA-damaging, targeted, and immune therapies. We further argue that successful sirtuin pharmacology will require context matching rather than indiscriminate activation or inhibition. Priorities include spatial and single-cell biomarker discovery, compartment-specific NAD+ measurements, PTM-resolved activity assays, structure-guided isoform-selective agents, and degrader strategies targeting non-catalytic scaffolding functions. Sirtuins should therefore be viewed as metabolic-epigenetic decision nodes rather than fixed oncogenes or tumor suppressors. However, the evidence remains predominantly preclinical, and our search identified no clinical-stage oncology trials of direct sirtuin modulators using prospective biomarker stratification, underscoring that this framework remains translationally aspirational rather than clinically validated.

Cholangiocarcinoma (CCA) is a highly aggressive, molecularly heterogeneous biliary tract malignancy and the second most common primary liver cancer, and it has an increasing global incidence and persistently poor prognosis. Recent updates of international guidelines, including those from the NCCN, ESMO, EASL, CSCO, BSG, and Japanese societies, along with rapid advances in precision oncology, have substantially changed the clinical management of CCA. This review systematically compares current global guidelines, highlighting both areas of consensus and regional differences in epidemiology, risk factors, screening strategies, diagnostic approaches, pathological and molecular classification, staging systems, surgical indications, systemic therapy, and multidisciplinary management. This review also summarizes recent advances in molecular diagnostics, including next-generation sequencing, liquid biopsy, circulating tumor DNA, extracellular vesicles, artificial intelligence-assisted imaging, radiomics, and emerging prognostic biomarkers. The evolving roles of immune checkpoint inhibitors, molecularly targeted therapies against FGFR2, IDH1, HER2, BRAF, NTRK, and MSI-H/dMMR, liver transplantation, locoregional treatment, and conversion (translational) therapy are also discussed. Finally, this review addresses current challenges, including drug resistance, limited access to molecular testing, regional disparities in healthcare resources, and the lack of universally accepted screening strategies. By integrating updated guideline recommendations with the latest clinical evidence, this review provides a comprehensive reference for evidence-based clinical decision-making and future translational research in CCA.

The advent of CRISPR/Cas9 genome editing has significantly transformed the landscape of cancer therapeutics by facilitating precise and programmable manipulation of disease-associated genetic modifications. This review comprehensively evaluates the current clinical and translational landscape of CRISPR/Cas9-based cancer therapies through an analysis of published literature and registered clinical trials. The current CRISPR/Cas9 applications in oncology are primarily centred on three mechanistic strategies: immune cell engineering for enhanced tumor recognition, direct targeting of oncogenic mutations, and modulation of tumor-supportive pathways. Analysis of 32 clinical trials indicates that CRISPR-based interventions have demonstrated encouraging safety profiles and early signs of clinical activity, particularly in ex vivo engineered immune-cell therapies. Notable examples include CRISPR-edited CAR-T cell products targeting CD19 and BCMA, which have achieved objective responses in relapsed or refractory hematological malignancies while demonstrating sustained persistence of edited cells in vivo. In contrast, clinical translation into solid tumors remains comparatively limited due to challenges associated with delivery efficiency, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Technological advancements, including multiplex genome editing, base editing, and prime editing have expanded the precision and versatility of CRISPR-based interventions, while integration with immunotherapy and nanotechnology-based delivery systems continues to broaden therapeutic potential. Despite these advances, several significant challenges still need to be addressed, including off-target editing, manufacturing scalability, delivery limitations, and regulatory considerations. Overall, CRISPR/Cas9 represents a promising yet evolving platform in oncology, with its future clinical success dependent on achieving a balance between precision, safety, scalability, and long-term therapeutic durability.

Personalized vaccines provide the advantage of patient-specific antigen selection to optimize immune responses, a strategy extensively explored in oncology through neoantigen-targeted peptide, mRNA, and dendritic cell platforms. Peptide vaccines provide simplicity and stability though often elicit limited cytotoxic T-cell responses. What is more, mRNA vaccines lead to rapid, multiplexed neoantigen delivery, endogenous antigen processing and eventually improved immunogenic coverage. Dendritic cell-based vaccines have the potency to prime potent T-cells although this technology requires labor-intensive manufacturing and extensive production timelines. Integration with immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses further enhances efficacy, suggesting that rational combinations may be more effective than single modalities. Recent advances in sequencing, computational epitope prediction, and bioinformatics pipelines have facilitated neoantigen prioritization and DC vaccine design, enabling more rapid and precise personalization. Hybrid vaccination strategies, such as ex-vivo mRNA-electroporated dendritic cells and in-vivo DC-targeted platforms, bridge the gap between manufacturing feasibility and potent immune activation. Emerging technologies, including AI-driven neoepitope prediction, receptor-targeted antigen delivery, biomaterial-based modulation, and distributed mRNA manufacturing, seem to be promising approaches to accelerate personalized vaccine development in future. From another point of view, lessons learned from the COVID-19 pandemic accelerated the development, large-scale deployment, and validation of mRNA vaccine platforms for infectious diseases. Host HLA diversity, prior immune history, and viral evolution create heterogeneity in immune responses, highlighting opportunities for semi-personalized or adaptive strategies. In this review, we provide a landscape of personalized vaccines, with a focus on DC-based platforms, and explore translational lessons for viral pathogens. A conceptual framework linking cancer immunotherapy and infectious disease preparedness is proposed, emphasizing hybrid personalization approaches, rapid manufacturing, and AI-enabled epitope selection. This perspective highlights how convergence of immunology, computational biology, and advanced vaccine technologies could expand the scope of personalized vaccination, from oncology to future epidemic and pandemic scenarios as well as the current challenges.

Lactylation, a unique post-translational alteration, has been identified as an important epigenetic regulator of cancer metabolism, immune evasion, and treatment resistance. Recent research reveals that ultrasound-based biophysical stimulation may change tumor microenvironmental variables that affect lactate metabolism and subsequent lactylation processes. The purpose of this study was to better understand the predictive significance of lactylation-associated genes in lung adenocarcinoma (LUAD) and how they could interact with ultrasound-mediated treatment response. Transcriptomic data from 867 LUAD samples were used to identify lactylation-related genes. Consensus clustering was used to separate LUAD cases into various lactylation subtypes. Differentially expressed genes were assessed for functional enrichment, mutation load, and immunological infiltration. A prognostic risk model was created using multivariate Cox regression analysis. Nineteen major lactylation-related genes divided patients with LUAD into three molecular subgroups with different clinical outcomes. A 10-gene prognostic model accurately predicted overall survival and was associated with stronger tumor stemness, increased mutational frequency, and decreased immunotherapy effectiveness in high-risk patients. Notably, computational predictions suggested that metabolic regulation might slow lactylation-driven tumor development, implying a synergistic treatment window. Lactylation-associated gene profiles may serve as prognostic biomarkers and therapeutic modulators in LUAD. The combination of ultrasound-based therapies targeting lactylation pathways could be a viable technique for improving precision oncology and overcoming resistance mechanisms in lung cancer therapy.

Despite remarkable advances in cancer drug treatment, including chemotherapy, targeted therapy, and immunotherapy, therapeutic resistance remains a formidable clinical barrier, limiting durable responses and long-term survival. Drug resistance can be broadly categorized as intrinsic, where tumors fail to respond to initial treatment, or acquired, which emerges during or after therapy due to adaptive or evolutionary processes. A comprehensive understanding of the multifactorial and dynamic nature of resistance is essential for improving treatment efficacy. In this review, we systematically examine the molecular and cellular determinants of drug response and resistance across 22 cancer types, highlighting key resistance mechanisms such as compensatory pathway activation, phenotypic plasticity, immune evasion, enhanced DNA damage repair, and the survival of drug-tolerant persister cells. These mechanisms are further contextualized across major therapeutic modalities, supported by clinical trials. We also present emerging strategies to overcome resistance, including rational drug combinations, novel agents, microbiome modulation, adaptive and intermittent therapies and advanced drug delivery systems, each illustrated with representative clinical studies. Moreover, we discuss cutting-edge tools that are revolutionizing resistance research, including single-cell and spatial multiomic profiling, patient-derived tumor organoid and xenograft (PDO/PDX) models, and artificial intelligence (AI)-powered predictive analytics. By integrating insights across molecular, cellular, and clinical dimensions, this review offers a strategic framework for understanding and tackling cancer drug resistance, with important translational implications for the future of precision oncology.

Exosome-mediated delivery of small interfering RNA (siRNA) has emerged as a promising therapeutic strategy for cancer treatment, offering precise gene silencing with minimal off-target effects. Exosomes, naturally secreted extracellular vesicles, provide biocompatible carriers that protect siRNA from enzymatic degradation and facilitate efficient uptake by tumor cells. Their natural tropism, driven by surface proteins such as integrins and tetraspanins, promotes cellular adhesion and interactions within the tumor microenvironment, facilitating the delivery of therapeutic cargo. Preclinical studies have demonstrated that exosome-delivered siRNAs can suppress oncogenes, inhibit tumor growth, reverse chemoresistance, and modulate immune responses by targeting stromal and immune components. Engineering approaches, including surface functionalization and hybrid exosome-nanoparticle systems, further enhance stability, payload capacity, and tumor-homing efficiency. Combination strategies with chemotherapy, immunotherapy, or phototherapy have shown synergistic effects, allowing simultaneous inhibition of survival pathways, promotion of apoptosis, and remodeling of the immunosuppressive microenvironment. Early-phase clinical studies indicate safety, effective biodistribution, and functional gene silencing, highlighting the translational potential of exosome-mediated siRNA therapeutics. Challenges such as scalable production, cargo heterogeneity, and regulatory considerations remain, but ongoing advances in exosome engineering and patient-derived vesicles are poised to overcome these barriers. This review aims to comprehensively summarize the current state, therapeutic applications, and translational prospects of exosome-mediated siRNA delivery in cancer.

Glioblastoma (GBM) is an aggressive and highly lethal brain tumor. Secondary glioblastoma (sGBM), which arises through malignant progression from lower-grade diffuse glioma, represents a clinically and biologically distinct subset of GBM. In this disease context, the protein tyrosine phosphatase receptor type Z1-mesenchymal-epithelial transition factor (PTPRZ1-MET; ZM) fusion has emerged as a recurrent oncogenic driver associated with adverse clinical outcomes. In this study, we analyzed 159 patients with sGBM, including 15 ZM-positive and 144 ZM-negative cases, and confirmed that ZM-positive tumors were associated with significantly shorter overall and progression-free survival. Transcriptomic profiling identified 359 genes upregulated in ZM-positive tumors, with enrichment in cell-cycle regulation and mitotic spindle-related pathways. To explore surrogate biomarkers associated with ZM fusion status, we benchmarked eight machine-learning classifiers and retained XGBoost as the primary feature-prioritization model. MET, PCDHGA3, and FAM3C emerged as the most informative biomarkers, and the fixed three-gene panel showed stable discriminative performance across cross-validation, nested evaluation, feature-pool sensitivity analyses, repeated random seeds, and class-weighted modeling. Protein-level validation in an independent formalin-fixed, paraffin-embedded (FFPE) cohort using multiplex and conventional chromogenic immunohistochemistry supported the pathology-compatible detection of elevated MET, PCDHGA3, and FAM3C expression in ZM-positive tumors. Collectively, these findings support a robust three-gene molecular signature that may facilitate the identification and stratification of ZM fusion-positive sGBM and provide biological insights with potential translational relevance for precision glioma diagnosis.

RAD51 is a central protein in the homologous recombination (HR) pathway and is essential for the accurate repair of DNA double-strand breaks (DSBs). Following DSB formation, DNA end resection generates single-stranded DNA substrates that facilitate the recruitment and assembly of RAD51 nucleoprotein filaments at sites of damage. This process results in the formation of discrete nuclear RAD51 foci, which serve as a widely accepted functional readout of HR activity and a surrogate marker of HR proficiency. Because defects in HR are common in several malignancies, particularly ovarian and breast cancers, assessment of RAD51 foci formation has emerged as an important approach for evaluating DNA repair capacity and predicting response to DNA-damaging therapies, including platinum compounds and poly(ADP-ribose) polymerase (PARP) inhibitors, whose efficacy is strongly influenced by HR repair status. This manuscript describes a simple, reliable, and reproducible immunofluorescence-based protocol for the detection and quantification of RAD51 nuclear foci in cultured ovarian cancer cells. The method involves induction of DNA damage by ionizing radiation (IR), followed by fixation, immunostaining with antibodies against RAD51 and γH2AX, confocal microscopy, and manual quantitative analysis of RAD51/γH2AX co-localized foci. The protocol can be applied under basal conditions or after genetic and pharmacological perturbations to determine their effects on HR function. Representative results demonstrate robust induction of RAD51 foci in HR-proficient ovarian cancer cells following DNA damage, whereas RAD51 depletion markedly reduces foci formation despite comparable levels of DSBs, confirming assay specificity. Overall, this protocol provides a robust and reproducible functional assay for assessing HR competency, with broad applications in preclinical and potentially translational cancer research.

Glycosylation is an important post-translational modification that can alter the biological activities of antibodies. In monoclonal antibody biotherapeutic products, glycosylation of the Fc-domain, which is often sensitive to manufacturing conditions, can alter product potency by affecting its interactions with host immune cells. Improving control of antibody glycosylation to produce more chemically defined products and to better understand glycan function is gaining interest, with chemoenzymatic glycan engineering emerging as a powerful technique. This chapter describes methods to obtain purified glycans, including isomers with asymmetric antennae, their enzymatic incorporation into monoclonal antibodies, and a natural killer T cell-based binding assay to determine FcγRIIIA (CD16A) binding affinity.

Breast cancer (BC) is the most common malignancy among women worldwide. Although observational studies have linked carnitine-related metabolites (CRMs) to BC, causal inference has been limited by confounding and reverse causality. This study used Mendelian randomization (MR) analysis to investigate the potential causal link between CRMs and BC. MR analysis was conducted using the Cancer Genome Atlas-BC and CRM-related datasets to explore the potential causal relationship between CRMs and BC. Variants were screened based on criteria encompassing genome-wide significance (p < 5&#xd7;10-8), independence (r 2 < 0.001, kb=10000), and sufficient strength (F-statistic > 10). Various MR techniques, including inverse-variance weighted, MR-Egger, simple mode, weighted mode, and weighted median approaches, were applied to assess these potential causal associations. Single-cell RNA sequencing (scRNA-seq) was employed to investigate the expression and biological functions of biomarkers linked to metabolites. The MR analysis suggested that genetically predicted elevated levels of octanoylcarnitine and decanoylcarnitine were associated with increased risk of BC. Functional enrichment analysis identified 12 candidate genes associated with these metabolites, which are involved in fatty acid &#x3b2;-oxidation (FAO) pathways. ScRNA-seq analysis revealed eight distinct cell subpopulations, with macrophages exhibiting the highest intercellular communication. Six biomarkers were identified as potential contributors to BC development: ACADM, FNIP2, RAPGEF2, RABGGTB, PPID, and ST6GALNAC3. This study provides evidence supporting potential causal associations between octanoylcarnitine and decanoylcarnitine and BC risk. Integrative single-cell transcriptomics revealed six CRM-associated biomarkers and their dynamic expression within tumor microenvironments. Additional experimental and clinical studies are needed to validate these observations and clarify their biological and translational relevance.

The programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) signaling pathway is a key mechanism underlying tumor immune escape. It suppresses anti-tumor immune responses through various mechanisms, including T-cell exhaustion, expanding regulatory T cells(Tregs), promoting M2 macrophage polarization, inhibiting natural killer(NK) cell function, and disrupting the balance of glycolysis/fatty acid oxidation metabolism. Immune checkpoint inhibitors(ICIs) targeting the PD-1/PD-L1 pathway have shown significant efficacy in the treatment of solid tumors. However, approximately 60%-70% of patients do not benefit due to drug resistance or immune-related adverse events(irAEs), and the heterogeneity of the tumor microenvironment(TME) further limits their effectiveness. Single-target blockade strategies are insufficient to comprehensively reverse immune escape, which highlights the urgent need for multidimensional interventions. Numerous studies have shown that various TCM active ingredients and compounds can regulate the PD-1/PD-L1 pathway through multiple targets to enhance immune responses. Their mechanisms involve modulating key signaling pathways, mediating epigenetic changes, reprogramming cellular metabolism, and reshaping the immunosuppressive microenvironment. Therefore, this review, focusing on the PD-1/PD-L1 pathway, systematically summarized the research progress on TCM active ingredients, compounds, and patent medicines in cancer immunotherapy. It aims to analyze their immunoregulatory networks, providing theoretical insights and translational directions for optimizing cancer immunotherapy strategies.

Hematological malignancies remain one of the leading causes of morbidity and mortality despite advances in targeted therapies, immunotherapy, and stem cell transplantation. Emerging evidence indicates that treatment efficacy and toxicity depend not only on the choice of therapy but also on its timing relative to the patient's internal circadian rhythm. The circadian clock orchestrates fundamental processes in hematopoiesis and immunity, such as stem-cell proliferation, leukocyte trafficking, DNA repair, and drug metabolism, while its disruption promotes malignant transformation, therapeutic resistance, and systemic toxicity. This narrative review synthesizes current understanding of circadian regulation in hematopoietic and immune systems, the mechanistic and preclinical foundations of chronotherapy in blood cancers, and the limited but growing body of clinical evidence linking treatment timing with outcome in leukemia, lymphoma, and transplantation. The review also examines practical challenges, including inter-individual variability, disease-induced circadian disruption, and hospital workflow constraints, while highlighting emerging technologies, such as transcriptomic clocks, wearable biosensors, and AI-driven scheduling algorithms, that are poised to enable personalized, time-aware therapy. By integrating temporal precision into existing therapeutic frameworks, chronotherapy may represent a promising investigational dimension of precision medicine in hematological oncology. However, its clinical value remains to be defined through prospective studies that incorporate validated circadian biomarkers, predefined timing windows, and clinically meaningful efficacy and toxicity endpoints.

In the era of immunotherapy, head and neck squamous cell carcinoma (HNSCC) has demonstrated clear benefits from immune-based treatments and is widely regarded as a tumor type with high immunotherapeutic potential. These tumors are characterized by robust and persistent inflammatory responses that actively drive tumor initiation and progression while concurrently shaping their sensitivity or resistance to therapy. Inflammation simultaneously creates therapeutic vulnerabilities and barriers by altering tumor behavior and reprogramming the immune microenvironment. This review examined HNSCC through a tripartite prism of inflammation, immunity, and tumor biology to demonstrate how chronic inflammatory cues rewire immune cells, reshape signaling circuits, and remodel tissue architecture, ultimately altering responses to immunotherapy. We first examined how immune cell reprogramming occurs under inflammatory pressure. Macrophages, regulatory T cells, exhausted CD8+ T cells, and specialized dendritic cell subsets can switch roles-from tumor-clearing sentinels to promoters of tumor growth, stemness, and invasion. This plasticity-sometimes transient, sometimes entrenched-determines whether the immune ecosystem favors elimination or tolerance, and consequently whether immune checkpoint blockade succeeds or fails. Next, we catalogued the inflammation-linked pathways and readouts that capture these state changes. Signaling hubs such as NF-&#x3ba;B/STAT3, IL-6/TNF&#x3b1;, TGF-&#x3b2;, HA-CD44, and PI3K-4EBP1-SOX2 orchestrate the trade-offs between proliferation and invasion and govern cancer stem cell dynamics. Corresponding biomarkers-PD-L1, CD163/CD68 ratios, LAMP3, ALDH/SOX2, Zeb1, Vimentin, and CD44 isoforms-become far more informative when resolved at single-cell and spatial scales, thereby enabling sharper patient stratification. We then mapped the pathological interplay among tumor, stromal, and immune compartments. Extracellular matrix reprogramming, CAF heterogeneity, and the spatial polarity of immune infiltrates generate discrete micro-niches with distinct functional consequences. Spatial profiling can convert static pathology into a dynamic atlas of therapeutic opportunities. Finally, we outlined translational directions. Targeting inflammation and the microenvironment-via TAM reprogramming, cytokine blockade, or STING/CD47 pathway modulation combined with immune checkpoint blockade (ICB)-offers a rational strategy to improve outcomes. Altogether, these strategies point toward an ecology-aware approach to precision immunotherapy for HNSCC-one that reads and reshapes the tumor's inflammatory language rather than ignoring it.