搜索结果：Critical reviews in oncology/hematology

The multifunctional scavenger receptor CD36 serves as a critical regulator in tumor progression by influencing processes such as fatty acid uptake, metabolic reprogramming, immune evasion, and metastasis. Conventional strategies to inhibit CD36, including use of monoclonal antibodies and small-molecule inhibitors, mainly impede the functional activity of this protein and are frequently hindered by compensatory mechanisms and emergence of resistance. The development of proteolysis-directed chimeras (PROTACs) represents a significant paradigm shift in therapy, transitioning from traditional protein inhibition to on-demand catalytic degradation of target proteins. This narrative review systematically examines the rationale, design, and therapeutic potential of applying PROTAC technology to induce the degradation of CD36 in cancer cells. Initially, we review the oncogenic implications of CD36 and the limitations of the existing inhibitors. Next, we outline the significant advantages associated with CD36 degradation compared to using the inhibitory strategy, such as overall functional elimination, avoidance of the compensatory mechanism, and possibility of prolonged effects. The review primarily focuses on addressing the strategic decision-making involved in the development of CD36-targeting PROTACs and includes a thorough discussion regarding the quality of the ligand (warhead) selection among known CD36 binders, selection of E3 ligase recruiters (e.g., cereblon [CRBN] and von Hippel Lindau [VHL]), and optimization of the linker. Subsequently, we indicate the opportunities of CD36 degraders in overcoming chemotherapy resistance, metastasis-activating cell growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing the efficacy of radiotherapy. Lastly, we discuss major issues, including target selectivity, maximizing pharmacokinetics (PK), potential development of resistance, and risks associated with physiological functions of CD36. We also present future directions, including TME‑activated prodrugs, dual‑target PROTACs, and combination therapies.

Anticancer dosing has historically prioritized the maximum tolerated dose (MTD), yet contemporary targeted therapies, immunotherapies, and antibody-drug conjugates frequently show nonmonotonic efficacy and toxicity relationships. We summarize the evolving evidence base and outline a patient-centered framework for dose optimization consistent with modern regulatory expectations. Narrative review of contemporary literature and regulatory principles for oncology dose optimization, focusing on exposure-response evaluation, pharmacokinetic-pharmacodynamic (PK/PD) modeling, biomarker/target engagement strategies, therapeutic drug monitoring (TDM), model-informed precision dosing (MIPD), pharmacogenetics, and contemporary early-phase trial designs integrating toxicity and efficacy. Accumulating evidence indicates that recommended doses for many agents remain anchored to MTD-era development, contributing to avoidable toxicity, treatment interruptions, and premature discontinuation. However, the evidentiary basis for dose individualization is heterogeneous: randomized dose-ranging and prospective TDM data are available for selected settings, whereas many proposed approaches remain supported mainly by exposure-response modeling, observational studies, or pharmacological plausibility. Exposure-response and PK/PD analyses often identify efficacy plateaus at doses below MTD for selected molecularly targeted agents and immune checkpoint inhibitors, while toxicity may continue to rise; conversely, cytotoxic drugs and antibody-drug conjugates may retain narrower exposure windows in which underdosing can compromise efficacy. TDM and Bayesian MIPD can address interpatient exposure variability, but current limitations include assay availability, uncertain target concentrations for many agents, turnaround time, cost, adherence confounding, and limited prospective validation. Pre-emptive pharmacogenetic testing is clinically established for selected high-evidence gene-drug pairs such as DPYD-fluoropyrimidines, whereas other biomarkers require further validation before routine adoption. Optimal dosing should shift from "highest tolerable" to "best for the patient," integrating drug-class-specific pharmacology, exposure, biomarkers, patient characteristics, and clinically meaningful outcomes within multidisciplinary workflows. Scalable implementation will require pragmatic infrastructure for TDM/MIPD, careful distinction between validated and investigational biomarkers, systematic medication reconciliation, and prospective randomized or pragmatic dose-optimization trials aligned with Project Optimus principles.

Dendritic cells (DCs) critically regulate immune dynamics within the tumor microenvironment (TME), yet the mechanisms governing the balance between effective anti-tumor immunity and immune tolerance remain incompletely defined. Existing reviews have largely examined DC biology, tumor immunology and neuroinflammation within disease-specific frameworks, leaving insufficient attention to how DC dysfunction may be compared across chronic pathological microenvironments. Here, we propose DC-driven immune rebalancing as a context-dependent framework for understanding how antigen-presenting cell states, inflammatory signaling, metabolic conditioning and immune-resolution circuits shape divergent disease outcomes. Within the TME, hypoxia, lactate accumulation, aberrant cytokine signaling and stromal-vascular constraints can reprogram DCs toward dysfunctional or tolerogenic states, thereby impairing antigen presentation, weakening T-cell priming and limiting durable anti-tumor responses. In neurodegenerative disease, immune imbalance is more commonly characterized by persistent peripheral-central inflammatory activation, regulatory insufficiency and defective resolution, rather than by tumor-like immune tolerance. We therefore do not argue that cancer and neurodegeneration share identical DC phenotypes. Instead, we suggest that both disease contexts can be compared through disrupted DC-centered immune-regulatory control layers, including inflammatory signaling, antigen-presenting capacity, metabolic rewiring and resolution failure. This distinction reframes DC-driven immune rebalancing as a testable organizing framework: immunogenic DC functions may need to be enhanced when effector immunity is required, whereas tolerogenic or regulatory programs may need to be reinforced when inflammatory restraint is therapeutically desirable. By clarifying both the shared control layers and the disease-specific outputs of DC dysfunction, this review provides a balanced conceptual basis for future biomarker-guided and context-specific immunomodulatory strategies.

KRAS mutations occur in approximately 25-30% of NSCLC cases, with the KRAS G12C substitution present in 10-13% of advanced non-squamous tumors. Historically, KRAS was considered an undruggable oncogene, associated with limited therapeutic options and poor outcomes. The clinical development of KRAS G12C inhibitors has changed this landscape, demonstrating that KRAS can be effectively targeted. Several inhibitors are in clinical development, showing heterogeneous efficacy and safety profiles. Despite clinically meaningful antitumor activity, the durability of benefit achieved with currently available agents remains limited. The therapeutic benefit of currently available KRAS inhibitors is constrained by the emergence of resistance mechanisms, including secondary RAS alterations, activation of bypass signaling pathways, metabolic adaptations, and phenotypic plasticity, leading to early disease progression in a substantial proportion of patients. To address these limitations, next-generation strategies are under active development. ON-state and pan-RAS inhibitors aim to improve suppression of oncogenic signaling and to retain activity in the context of resistance to first-generation compounds. In parallel, multiple combination approaches are being evaluated, including associations with chemotherapy, immune checkpoint inhibitors, and novel pharmacological classes designed to counteract pathway reactivation, enhance response depth and improve clinical benefit. This review provides a comprehensive and updated overview of KRAS G12C inhibition in NSCLC, summarizing biological mechanisms underlying KRAS oncogenesis, clinical evidence supporting currently approved therapies, emerging drug development strategies, mechanisms of therapeutic resistance, and evolving combination approaches. Collectively, these advances are transforming KRAS G12C-mutant NSCLC from a refractory molecular subtype into a disease increasingly amenable to precision oncology strategies.

To evaluate the role of probiotic supplementation in cancer patients and its clinical effects. English-written clinical trials, pooled-, or meta-analyses of clinical trials assessing probiotic treatments in cancer patients. PubMed, Scopus, and Web of Science databases up to September 2025. Narrative synthesis of included studies, stratified by assessed outcomes. 3 clinical trials, 1 in vivo study followed by a clinical trial, 2 meta-analyses and 1 pooled analysis. Across chemotherapy settings, probiotic supplementation was associated with a reduction in clinically relevant diarrhea, with the most consistent signal for severe diarrhea and for selected subgroups (e.g., patients with colostomy during irinotecan-based therapy). Meta-analytic evidence also supported improvements in other gastrointestinal (GI) symptoms (nausea/vomiting, bloating, anorexia). In surgical oncology, perioperative probiotics/synbiotics were associated with faster GI functional recovery and favorable recovery-related markers in individual trials, while pooled randomized evidence in colorectal surgery indicated fewer postoperative infections and shorter length of stay; effects on anastomotic leak were inconsistent. Controlled clinical studies did not report probiotic-strain invasive infections, although rare serious events have been described in broader evidence. Heterogeneity in study designs, formulations, and outcome definitions; limited reporting of resource-utilization outcomes and adverse-event attribution; few large-scale trials; scarce direct oncologic efficacy endpoints. Probiotics appear to be a promising adjunct for supportive care in selected cancer pathways, particularly for GI toxicity and perioperative outcomes. Strain-defined, adequately powered trials with harmonized endpoints are needed to inform guideline-ready use.

Papillary thyroid cancer (PTC) is the most prevalent endocrine malignancy, accounting for over 90% of thyroid cancers. While differentiated thyroid cancers (DTCs) typically have favorable outcomes, a significant subset progresses to radioactive iodine-refractory (RAIR) disease, characterized by impaired iodine uptake and a 10-year survival rate below 10%. Genetic alterations and dysregulated signaling pathways underlie this transition. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), play critical regulatory roles in tumor biology and may be transported via exosomes, facilitating intercellular communication and contributing to RAIR-PTC. This systematic review, conducted according to PRISMA 2020 guidelines, evaluated the role of exosomal ncRNAs in RAIR-PTC. A comprehensive search of PubMed, PubMed Central, and Google Scholar identified studies published within the past 15 years in English. Following stringent quality appraisal, studies with a non-bias score above 40% were included. Of 961 identified publications, 96 high-quality studies met inclusion criteria. Evidence indicates that therapy resistance in RAIR-PTC is driven by convergent ncRNA regulatory networks that suppress sodium-iodide symporter (NIS) expression and activate oncogenic pathways, most notably MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. Multiple ncRNAs converge on key regulatory nodes, forming redundant circuits that sustain dedifferentiation, metabolic adaptation, and impaired iodide transport. Several consistently dysregulated ncRNAs directly or indirectly regulate NIS expression and trafficking, highlighting actionable targets. Exosomes emerge as biologically compatible, programmable delivery vehicles capable of transporting therapeutic ncRNA payloads independent of endogenous packaging mechanisms. These findings support a precision therapeutic paradigm in which engineered exosomes reprogram ncRNA networks to restore iodine-handling pathways and overcome therapy resistance in RAIR-PTC.

Lung Cancer Non-smokers (LCNS) is a developing worldwide health issue. LCNS is caused by a different combination of environmental, genetic, and molecular variables than smoker-related lung cancer, necessitating a change in preventive and treatment approaches. Particularly among women and those living in contaminated metropolitan areas, the incidence is rising. Radon, indoor biomass fuels, occupational carcinogens, ambient air pollution, and novel contaminants are examples of non-tobacco dangers. These exposures create distinct molecular and epigenetic landscapes by promoting oxidative stress, inflammation, and DNA damage. Molecularly, LCNS usually exhibits no tobacco-related mutational markers and a modest tumor mutational load. Actionable drivers, including EGFR, ALK, ROS1, RET, and HER2, are frequently included. EGFR signaling, PI3K/AKT/mTOR, MAPK/ERK, Hippo-YAP/TAZ, ferroptosis, and non-coding RNA networks are among the controlled signaling pathways that frequently direct tumor formation rather than widespread genetic instability. Heterogeneity and resistance are facilitated by epigenetic remodeling and transcriptional flexibility, which enable tumors to adjust to their surroundings and treatment. This study compiles the current understanding of LCNS etiology, molecular characteristics, and signaling pathways and identifies gaps that hinder clinical translation. In order to capture exposure-molecule interactions, it emphasizes the necessity of combining environmental exposomics with multi-omics tumor profiling. Intratumoral heterogeneity may be resolved, exposure-specific cell states may be elucidated, and novel therapeutic targets may be identified through advances in single-cell and spatial omics. Precision oncology requires molecular and liquid biopsy biomarkers, as early diagnosis and LCNS-specific screening remain difficult in clinical practice. Pathway-focused treatments for non-smokers, environmental interventions, and exposure-informed risk models are some potential future possibilities. Research, prevention, and patient treatment are improved worldwide when LCNS is framed as a unique, environmentally driven illness.

The causal involvement of tertiary lymphoid structures (TLS) in the context of neoadjuvant immunotherapy for hepatocellular carcinoma (HCC) remains inadequately defined, and a comprehensive clinical translation framework is currently absent. This review addresses two primary questions: (1) Does the formation of TLS causally influence the efficacy of immunotherapy? (2) What strategies can facilitate the clinical implementation of TLS? A systematic literature search was conducted using PubMed and Web of Science databases, covering all relevant peer-reviewed studies up to March 2026, focusing on TLS in HCC neoadjuvant immunotherapy. Key quantitative findings indicate that responders exhibit an enrichment of intratumoral TLS; a high density of TLS is associated with a 100% recurrence-free survival rate at 30 months; surgical patients demonstrate a major pathological response rate of 33.3% and an overall survival rate of 86% at four years. Furthermore, experimental depletion of B cells in murine HCC models abolishes antitumor efficacy, thereby establishing TLS as a causal mediator in preclinical settings. These findings are integrated into a conceptual framework describing the intratumoral immune cycle, and a clinical roadmap is proposed, which includes standardized TLS detection methods (hematoxylin-eosin-saffron staining combined with CD20/CD23 immunohistochemistry) and potential TLS-targeting therapeutic strategies. This review provides oncologists and researchers with an evidence-based framework to incorporate TLS into precision neoadjuvant immunotherapy for HCC, advancing the field from mere associative observations to establishing causality and transitioning TLS from a biomarker to a therapeutic target.

Liver metastasis is a major determinant of cancer mortality, driven not only by tumor-intrinsic traits but also by dynamic reprogramming of the hepatic tumor microenvironment. Proprotein convertase subtilisin/kexin type 9 (PCSK9), classically known for its role in cholesterol metabolism, has recently emerged as a key regulator of this process. Beyond hepatocyte lipid homeostasis, PCSK9 influences multiple liver-resident and infiltrating cell populations, including sinusoidal endothelial cells, hepatic stellate cells, macrophages, and lymphocytes, collectively promoting immune evasion, angiogenic remodeling, vessel co-option, and metastatic progression. Recent preclinical evidence indicates that PCSK9 suppresses antitumor immunity by limiting MHC class I expression, impairing CD8⁺ T-cell infiltration and cytotoxic function and favoring immunosuppressive macrophage and regulatory T-cell programs within the hepatic niche. In parallel, PCSK9 enhances endothelial activation and vascular co-option, contributing to resistance against anti-angiogenic therapies in liver metastases. This work synthesizes current knowledge on PCSK9-mediated regulation of the liver metastatic microenvironment, highlighting its pleiotropic effects across metabolic, vascular, and immune axes. We further discuss emerging therapeutic strategies targeting PCSK9, including clinically approved monoclonal antibodies, siRNA-based approaches, and next-generation nanoparticle delivery systems designed for cell-specific modulation within the liver. These findings position PCSK9 as a central metabolic-immune node linking cholesterol homeostasis to metastatic niche formation. Targeting PCSK9, particularly through precision delivery platforms, represents a promising avenue to enhance antitumor immunity, overcome therapy resistance, and improve outcomes in liver metastasis and primary liver cancers.

Classic BCR::ABL1-negative myeloproliferative neoplasms (MPNs)-polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis-are clonal haematopoietic stem cell disorders with marked heterogeneity in clinical phenotype, disease trajectory, and therapeutic response. Genomic stratification by driver and cooperating mutations only partially accounts for this variability, leaving gaps in predicting thrombotic risk, fibrotic progression, leukaemic transformation, and treatment benefit. Proteomics bridges this gap by providing function-proximal readouts of protein abundance, post-translational modifications, pathway activity, and intercellular signalling that genomics and transcriptomics cannot capture, positioning it as a theranostic platform in which the same molecular readouts simultaneously inform diagnostic stratification and therapeutic decision-making. We propose a five-stage translational framework spanning from discovery-scale mass spectrometry and affinity-based plasma profiling to targeted validation, multicentre standardisation, and machine learning-integrated clinical panels. Proteomic evidence is synthesised across the following four disease axes: clonal fitness in haematopoietic stem and progenitor cells; bone marrow microenvironmental remodelling and fibrosis; chronic inflammation and thrombosis; and leukaemic transformation. We further describe how phosphoproteomics reveals resistance mechanisms to JAK inhibitors, including AXL-MAPK bypass and PP2A-autophagy-mediated tolerance, and how protein-level biomarkers (BCL2-BCL-XL, RAS-ERK, CAMK2G, and ROCK1/2) can guide individualised therapeutic selection. Affinity-based platforms (Olink PEA and SomaScan) and spatially resolved technologies (CODEX and single-cell proteomics) complement discovery proteomics. At present, however, this evidence base is constrained by small and heterogeneous cohorts, limited cross-platform reproducibility, and a scarcity of independent external validation for candidate protein panels. Realising this vision will require multicentre standardisation, analytically validated panel assays, and prospective clinical studies that translate molecular findings into decision-grade tools for patients with MPNs.

Mitophagy, the selective autophagic clearance of damaged or superfluous mitochondria, may influence lymph node metastasis (LNM) by linking mitochondrial quality control to metabolic adaptation and immune evasion. In the lipid-rich and intermittently hypoxic lymph node niche, metastatic tumor cells often increase fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). This metabolic shift raises mitochondrial workload and reactive oxygen species (ROS) stress, thereby increasing the demand for mitochondrial quality control. This review summarizes canonical PINK1/Parkin-dependent ubiquitin signaling and receptor/lipid-dependent mitophagy pathways, including BNIP3/NIX, FUNDC1, PHB2 and cardiolipin-mediated mechanisms. We further discuss how these pathways cooperate with DRP1-mediated mitochondrial fission, endoplasmic reticulum (ER)-mitochondria contacts and FAO/OXPHOS reprogramming during LNM. Moderate mitophagy flux may support early metastatic seeding and micrometastatic persistence by limiting ROS, preserving mitochondrial membrane potential and maintaining bioenergetic fitness. In contrast, chronic excessive mitophagy flux may restrict tumor outgrowth by depleting functional mitochondrial mass, whereas insufficient mitophagy flux may increase mitochondrial DNA leakage, cGAS-STING activation and immune visibility. We also highlight how mitophagy may attenuate mitochondrial DNA-cGAS-STING signaling, impair dendritic-cell maturation and cross-presentation, and promote a regulatory T-cell-biased immune-tolerant lymph node microenvironment. Finally, we propose a practical LN-Mitophagy Score integrating mitophagy, FAO and immune markers to guide node-targeted, stage-specific, short-course and reversible interventions, including perioperative sentinel lymph node (SLN) window trials. Key challenges include in vivo mitophagy flux quantification, safe FAO/mitochondrial modulators and immune off-target effects.

The vitamin D receptor (VDR) is a key regulator of cellular growth and differentiation, and accumulating evidence links vitamin D signaling to tumor biology. However, the specific contributions of VDR across diverse cancers remain incompletely understood. This narrative review synthesizes current knowledge on the dualistic mechanisms of VDR in oncogenesis, integrating preclinical, translational, and early-phase clinical evidence across solid tumors and hematologic malignancies. In many contexts, ligand-activated VDR predominantly performs tumor-suppressive functions by inducing cell cycle arrest, promoting apoptosis, inhibiting metastasis, enhancing DNA repair capacity, and modulating epigenetic landscapes. Paradoxically, in specific tumor contexts, VDR may foster pro-oncogenic phenotypes through the establishment of immunosuppressive microenvironments or the perpetuation of oxidative stress. Preclinical evidence indicates that VDR activation may enhance the sensitivity of tumor cells to radiotherapy and chemotherapy. Translational and early-phase clinical evidence, predominantly from breast and colorectal cancer, identifies VDR as a promising therapeutic target and prognostic biomarker, although these findings remain hypothesis‑generating and require further validation. A deeper understanding of VDR biology is critical for clarifying its tumor-specific roles. Defining these mechanisms will not only improve prognostic accuracy but also enable the development of targeted interventions, ultimately advancing the use of VDR-based strategies in precision oncology.

Breast cancer remains the most commonly diagnosed cancer among women in the United States and the second leading cause of cancer-related deaths. Despite advances in treatment, significant disparities persist in breast cancer outcomes across racial, ethnic, and socioeconomic groups. This review aims to provide an updated examination of these disparities, focusing on differences in incidence, mortality, screening, and treatment. Data from SEER and other national databases show that while Non-Hispanic White women have the highest incidence rates, Black women experience a 36% higher mortality rate. Contributing factors include poor access to high-quality care, socioeconomic barriers, and biological differences, such as a higher prevalence of aggressive breast cancer subtypes like triple-negative breast cancer in Black women. Differences in screening rates further exacerbate these outcomes, with minority women being less likely to receive timely mammograms and appropriate follow-up care. Disparities are perpetuated further by systemic barriers, including healthcare access, structural inequalities, and implicit biases in patient-provider relationships. In addressing these issues, the paper proposes strategies such as improving access to early screening, enhancing clinical training to address racial bias, and implementing policies to improve healthcare infrastructure for underserved populations. By emphasizing the need for equitable access to care and targeted interventions, this review provides a comprehensive framework for reducing breast cancer disparities and improving outcomes for minority women in the U.S.

Gastric cancer (GC) remains a major cause of cancer-related mortality, largely due to late-stage diagnosis and the emergence of primary or acquired resistance to standard chemotherapies. Increasing evidence identifies extracellular vesicles (EVs), particularly exosomes, as central mediators of intercellular communication within the tumor microenvironment (TME). Extracellular vesicles (EVs) represent a heterogeneous population of membrane-bound particles that include exosomes, microvesicles, and apoptotic bodies, which differ in size, biogenesis, and functional properties. In this review, the term EVs is used as a comprehensive definition, while exosomes are referred to as a specific subtype originating from the endosomal pathway. Tumor-derived exosomes enriched in proteins, lipids, and nucleic acids profoundly reprogram infiltrating immune cells, shaping a highly immunosuppressive niche that supports tumor progression. In GC, exosomal immune checkpoint ligands, oncogenic non-coding RNAs, and vesicle remodeling driven by Helicobacter pylori infection collectively rewire immune surveillance, fostering a permissive microenvironment that sustains tumor growth and therapeutic resistance. At the clinical level, circulating EVs are emerging as powerful liquid-biopsy tools, supporting early detection, prognostic classification, and the prediction of responses to immune checkpoint inhibitors. Here, we discuss current insights into EV biogenesis and cargo sorting in GC, delineate how EVs reshape anti-tumor immunity and promote immune escape, and explore the translational potential of targeting EVs or their cargos as innovative therapeutic strategies in this aggressive malignancy.

Oropharyngeal squamous cell carcinoma (OPSCC) comprises two biologically distinct entities, HPV-positive and HPV-negative disease, which differ in etiology, immune microenvironment, molecular drivers, and clinical behavior. This narrative review summarizes current evidence on immunotherapeutic strategies in OPSCC, focusing on subtype-specific biological rationale and emerging treatment approaches. A literature search of PubMed/MEDLINE, Embase, Cochrane Library, ClinicalTrials.gov, and major oncology meeting abstracts was conducted for studies published from January 2000 to February 2026. PD-1/PD-L1 inhibitors represent the current standard of care in recurrent/metastatic disease, with HPV-positive tumors generally showing more favorable outcomes, likely reflecting a more inflamed and antigen-rich tumor microenvironment. However, HPV status remains primarily a prognostic rather than a validated predictive biomarker for checkpoint inhibitor benefit. In contrast, HPV-negative OPSCC is more frequently characterized by immune exclusion, EGFR dependence, hypoxia, and activation of MET/HGF and TGF-β pathways, supporting the development of EGFR-centered and bifunctional strategies to overcome resistance. Emerging agents such as ficerafusp alfa, petosemtamab, and amivantamab have demonstrated promising early clinical activity, particularly in biomarker-enriched or post-immunotherapy settings. In HPV-positive disease, therapeutic vaccines targeting E6/E7 oncoproteins have shown encouraging immunogenicity and preliminary antitumor activity, especially when combined with PD-1 blockade. Overall, the immunotherapeutic landscape of OPSCC is evolving toward a biomarker-driven framework integrating viral status, immune contexture and pathway activation to enable more precise and personalized treatment strategies.

Chimeric antigen receptor macrophages (CAR-Ms) are an emerging myeloid cell therapy designed to exploit the inherent plasticity of macrophages in solid tumors. By integrating antigen-specific recognition with macrophage-mediated phagocytosis, antigen presentation, and local immune remodeling, CAR-Ms coordinate tumor killing with reprogramming of the tumor microenvironment. Advances in CAR design, intracellular signaling, cellular platforms, and gene delivery have enabled preclinical evaluation in immunocompetent models and early clinical testing. CAR-Ms can enhance T cell and NK cell infiltration, promote antigen spreading, and sensitize tumors to immune checkpoint blockade. Early clinical studies, including HER2-targeted CT-0508, demonstrate feasible manufacturing, acceptable safety, tumor infiltration, and immune remodeling, though objective efficacy remains limited. Major challenges include maintaining antitumor polarization, persistence, scalable manufacturing, target selection, and safety control. Continued optimization of CAR-M design and exploitation of myeloid plasticity will be critical to realizing their potential as solid tumor immunotherapy platforms.

Despite the transformative impact of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC), durable responses remain limited to a subset of patients. Resistance-either intrinsic or acquired-continues to undermine the full therapeutic potential of immunotherapy. The cancer-immunity cycle provides a useful conceptual scaffold to dissect the multistep requirements for effective antitumor immunity. Recent advances in single-cell technologies, spatial profiling, longitudinal immune monitoring, and real-world clinical datasets have uncovered additional layers of complexity, including non-canonical pathways involving tumor metabolism, stromal architecture, vascular remodeling, epigenetic plasticity, microbiome-immune crosstalk, and host-related determinants of response. In this review, we provide an updated and integrated synthesis of both primary and acquired resistance mechanisms across each phase of the cancer-immunity cycle. We emphasize pathways that have gained mechanistic or clinical relevance in recent NSCLC literature and consolidate them in an updated reference figure (Figure 1). To strengthen translational relevance, we additionally include a dedicated section on host-related determinants of ICI efficacy-including immunosenescence, performance status, comorbidity burden, systemic inflammation, body composition, and concomitant medications-and a stepwise summary of representative primary versus acquired mechanisms with NSCLC clinical anchors (Table 1). Our goal is to frame resistance not as a single lesion, but as a dynamic tumor-host system that must be mapped to inform biomarker development and rational combination strategies.

Mitochondrial DNA (mtDNA) is emerging as a relevant component of the molecular landscape in non-small cell lung cancer (NSCLC). Due to its inherent vulnerability to environmental carcinogens, the mitochondrial genome accumulates alterations-such as D-loop variants and Electron Transport Chain variants- increasingly identified as potential mediators of tumor development and metabolic shifts. Recent findings highlight specific areas with potential for clinical application. In diagnostics, emerging models based on cf-mtDNA fragmentomics and tRNA-derived fragments have shown promising capabilities for early-stage detection. Prognostically, somatic variants in Complex I and specific mitochondrial lncRNA signatures have been evaluated as independent indicators of overall survival and metastatic risk. Furthermore, in regard to therapeutics, mitochondrial mass may potentially support chemotherapy election. Additionally, landmark evidence regarding the horizontal transfer of mitochondria to tumor-infiltrating lymphocytes offers a novel framework for understanding resistance to immunotherapy. While these preliminary results provide a promising roadmap for molecular stratification, their integration into routine practice remains a goal that requires further prospective validation in larger, multi-ethnic cohorts to ensure reproducibility and to distinguish functional drivers from passenger variants. Collectively, these emerging findings suggest that mtDNA analysis represents a valuable complementary approach to precision oncology in lung cancer.

Immune checkpoint blockade therapy has revolutionized cancer treatment and demonstrated significant clinical efficacy. However, conventional monoclonal antibody therapeutics still face numerous limitations. Peptide inhibitors, with their low molecular weight, ease of synthesis, cost-effectiveness, and minimal immunogenicity, offer a promising alternative by combining the high specificity of antibodies with the favorable tissue penetration of small molecules. As such, they represent a key direction for overcoming existing therapeutic bottlenecks and developing next-generation immunotherapies. Despite facing key challenges in clinical translation, particularly regarding metabolic stability and oral bioavailability, peptide-based inhibitors hold considerable potential to bridge the gap between antibodies and small-molecule drugs, positioning them as an important component of next-generation cancer immunotherapy. Currently, research in this field is increasingly shifting from traditional empirical screening to intelligent precision design, employing strategies such as rational design based on hotspot amino acids, AI-assisted drug discovery, and advanced delivery systems to optimize the activity, stability, and targeting properties of peptides. This review systematically outlines recent advances in immune checkpoint peptide-based inhibitors, aiming to provide a theoretical foundation for the rational design and clinical translation of this emerging class of therapeutics.