SLFN11, a member of the evolutionarily conserved SLFN gene family, is an interferon-stimulated early response gene. This review comprehensively explores its multifaceted roles. Structurally, its three distinct domains endow it with diverse functions. Epigenetic modifications, post-translational alterations, and multiple signaling pathways intricately regulate SLFN11 expression and activity. In terms of functions, it plays crucial roles in the DNA damage response during replication stress, distinct from traditional pathways. It also serves as a protector in the antiviral response and a valuable biomarker for predicting the efficacy of DNA-damaging agents and patient prognosis in various cancers. Beyond these, SLFN11 has non-canonical functions, including immune regulation, modulation of oncological behaviors, involvement in apoptosis, protection against proteotoxic stress, and association with Fanconi anemia. Looking ahead, SLFN11 holds great promise as a biomarker for personalized medicine, but challenges like developing accurate detection methods remain. In immunotherapy, understanding its dynamic changes is essential for optimizing treatment. Strategies to overcome SLFN11-low expression, such as epigenetic modulation, also need further investigation, which may open new avenues for disease treatment.

Clinical practice guidelines for nonsmall cell lung cancer (NSCLC) and small cell lung cancer include recommendations based on high-level clinical trial evidence, but complex clinical questions are frequently seen in real-world practice that are not clearly answered by prospective trial data. To address these questions, the Bridging the Gaps Lung Cancer Consensus Conference 2024 (BtG LCCC 2024) convened to develop US-focused expert guidance for clinical situations in which level 1 evidence is lacking. At BtG LCCC 2024, a multidisciplinary expert panel discussed ongoing clinical issues in small cell lung cancer management, targeted therapy in EGFR-mutated NSCLC, management of early stage NSCLC, identification and management of non-EGFR oncogene-driven NSCLC, and use of immunotherapy in advanced/metastatic NSCLC. By using a modified Delphi process, 12 consensus recommendations were developed with the goal of providing guidance on the use of novel diagnostic methods and treatments for clinicians who manage lung cancer. This report reviews these areas of consensus and discusses ongoing questions about ways to apply current clinical evidence.

CT-guided transthoracic lung biopsy (CT-TTNB) is an essential method for the diagnosis of pulmonary nodules and masses. With a sensitivity of 85-97% and a specificity of 85-100%, it offers high diagnostic accuracy. By using core-needle biopsies, high-quality tissue samples can be obtained that enable molecular analyses for personalised therapy.At the same time, lung ablation has established itself as a valuable minimally invasive therapy. Procedures such as radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation enable targeted tumour destruction, particularly in inoperable patients with NSCLC or lung metastases. Studies have shown a high level of local tumour control with acceptable complication rates. The combination of imaging and interventional technique significantly improves patient safety and treatment outcomes and offers good results with low complication rates.Overall, CT-guided puncture and ablation are integral components of modern lung cancer diagnostics for primary and secondary lung tumours, while offering a new treatment option and therapy. They offer precise, low-risk alternatives to invasive procedures and can therefore make a significant contribution to effective patient care.

Tumor-associated macrophages (TAMs), derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2 (CCL2) and colony-stimulating factor-1 (CSF-1), are pivotal components of the tumor microenvironment (TME). Functionally polarized into distinct subtypes, TAMs play dual roles: proinflammatory M1-type TAMs enhance antitumor immunity through the secretion of cytokines such as interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) and direct tumor cell cytotoxicity, whereas M2-type TAMs promote tumor progression by facilitating angiogenesis, metastasis, and immunosuppression. This polarization is dynamically regulated by different cytokines, various signaling pathways, and metabolic cues within the TME. Spatial distribution analyses revealed that M2-like TAMs predominantly infiltrate hypoxic and stromal regions, where they secrete factors such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), and matrix metalloproteinases (MMPs) to remodel the extracellular matrix and suppress immune responses via programmed death-ligand 1 (PD-L1) and arginase-1 upregulation. Crucially, TAMs interact extensively with immune cells; M2-TAMs secrete interleukin-10 (IL-10) and TGF-β to inhibit cytotoxic T lymphocytes while expanding regulatory T (Treg) cells and impairing natural killer (NK) cell function via altered antigen presentation. Conversely, M1-TAMs synergize with dendritic cells to enhance T-cell priming. Therapeutically, targeting TAMs offers promising strategies, including colony-stimulating factor-1 receptor (CSF-1R) inhibitors, CCL2 antagonists, and nanoparticle-mediated repolarization of M2-TAMs toward the M1 phenotype. Emerging genetic approaches, such as clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9 (CRISPR-Cas9) editing, aim to disrupt protumorigenic pathways in TAMs. Additionally, TAM-related biomarkers (e.g., CD206 and CD163) are being evaluated for their prognostic and predictive utility in immunotherapies. Despite progress, challenges persist owing to TAM plasticity and TME heterogeneity across cancers. This review synthesizes TAM biology, immune crosstalk, and therapeutic advancements, providing a foundation for novel oncology strategies aimed at reprogramming TAMs to overcome treatment resistance and improve clinical outcomes.

This review provides a comprehensive synthesis of current knowledge on immunotherapy resistance in non-small cell lung cancer (NSCLC), a disease that accounts for approximately 85% of all lung cancer cases and remains the leading cause of cancer-related death worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved survival for a subset of patients with advanced NSCLC, over 70% of cases ultimately exhibit primary or acquired resistance, underscoring the urgent need to understand the underlying mechanisms. The review categorizes resistance into tumor-intrinsic and tumor-extrinsic processes and provides an in-depth mechanistic analysis of how factors such as tumor antigen loss, impaired antigen presentation, cGAS-STING pathway dysregulation, metabolic reprogramming in tumor microenvironment (TME), immune cell exhaustion, and microbiomes collectively contribute to immune escape. In parallel, the influence of the lung and gut microbiome on shaping immunotherapy responses is discussed, with emphasis on microbial dysbiosis, immunosuppressive metabolite production, and TME remodeling. Therapeutic strategies to overcome resistance are also discussed, including combination approaches involving chemotherapy, radiotherapy, and antiangiogenic agents, as well as epigenetic modulators (HDAC and BET inhibitors). Moreover, the review explores bispecific antibodies, antibody-drug conjugates, and small-molecule agents that enhance T cell function or disrupt immunosuppressive signaling networks. By integrating insights from preclinical models and clinical trials, the review underscores the necessity of biomarker-guided patient stratification, combination immunotherapy approaches, and interventions that restore tumor immunogenicity. It concludes that a multipronged therapeutic strategy, one that addresses both immune evasion and TME-induced suppression, holds the greatest promise for improving response durability and advancing personalized immunotherapy for NSCLC.

Biomolecular phase separation has emerged as a fundamental mechanism governing intracellular spatial organization and functional compartmentalization, and is increasingly recognized as a critical factor in tumor initiation and progression. Through multivalent molecular interactions, biomolecular phase separation contributes to the formation of condensates that mediate the assembly of membraneless organelles, coordination of signaling pathways, and transcriptional programs. Under physiological conditions, condensation contributes to the maintenance of gene expression homeostasis, stress adaptation, and metabolic balance. In cancer cells, however, biomolecular condensates (BMCs) often exhibit aberrant behavior, accompanied by alterations in their structure, components, and regulatory mechanisms. Such perturbations may disrupt cellular homeostasis and influence key biological processes including gene regulation, signal transduction, metabolic reprogramming, and immune responses, thereby modulating various cancer hallmarks. Although the mechanistic understanding of BMCs remains incomplete, their intrinsic plasticity and environmental sensitivity make them attractive therapeutic targets for cancer treatment. This review provides a comprehensive overview of the regulatory factors and functional mechanisms of BMCs in cancer biology, with a particular focus on their involvement in diverse cancer hallmarks. This review further summarizes emerging therapeutic strategies targeting condensation, aiming to inspire novel treatment opportunities.

Natural killer (NK) cells are a crucial part of the innate immune system and serve as an important effector for killing tumor cells through direct cytolytic activity or immunomodulatory signaling to T cells and antigen presenting cells. NK cells are correlated with increased tumor control and better overall patient survival across various types of cancers including non-small cell lung cancer (NSCLC). Despite their promising potential for anti-tumor killing, NK cell function is often diminished within the tumor microenvironment. There are many factors that lead to decreased tumor-infiltrating NK cell killing, including immunoinhibitory factors from tumor cells and resident tissues, acquired immune tolerance, NK cell exhaustion, and the hypoxic state of the tumor microenvironment. Unleashing NK cell activity therefore has high potential to create a new class of immunotherapy that could combat both primary and acquired resistance to current checkpoint inhibitors. In this review we discuss mechanistic details of NK cell tumor killing, NK cell immunosuppression, and gaps in knowledge regarding highly complex microenvironment-specific effects on NK cell function. We also discuss the promise and limitations of emerging NK-cell based therapeutic strategies.

Extramedullary involvement (extramedullary disease, EMD) is an aggressive subtype of multiple myeloma (MM) characterized by myeloma subclones proliferating independently of the bone marrow microenvironment, often associated with high-risk cytogenetic abnormalities, immune evasion, and treatment resistance. While significant breakthroughs have been achieved in MM treatment with the sequential approval of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, prognosis remains poor once EMD develops. Even in the era of immunotherapy, the survival benefit for EMD patients has not shown significant improvement. This review systematically summarizes therapeutic options for MM patients with EMD, aiming to provide evidence-based guidance for EMD treatment.

SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT) is a rare and highly aggressive malignancy characterized by early distant metastasis and a poor prognosis, with a median overall survival (OS) of only 4-7 months. Traditional therapies offer limited benefit, while emerging data suggest the efficacy of combined immunotherapy, chemotherapy, and anti-angiogenic approaches. We report a case of a 52-year-old male with a heavy smoking history who presented with loss of consciousness and limb convulsions. Imaging revealed brain metastasis and a thoracic tumor. After surgical removal of the brain lesion and a lung biopsy, the patient was diagnosed with SMARCA4-UT, showing no targetable driver mutations and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) < 1%. The patient underwent first-line treatment with tislelizumab, bevacizumab, carboplatin, and paclitaxel. Despite discontinuation of bevacizumab due to a tumor cavity, the patient achieved partial remission (PR) after six cycles. Notably, consolidative thoracic radiotherapy (TRT) was administered following systemic disease control to enhance local control. After 5 months of maintenance therapy, oligoprogression of the primary lung lesion was detected and the progression-free survival (PFS) of first-line treatment reached 14 months. The patient then performed salvage surgery for local lesion and continued with maintenance treatment. As of May 2025, the patient has survived for 31 months since the initial diagnosis.

Lung cancer, a leading cause of cancer death, displays profound histologic and molecular heterogeneity across adenocarcinoma, squamous, and small-cell types. Clinically, tumours can shift between these states, reflecting lineage plasticity-the reprogramming of differentiated cells to alternate identities. Pre-existing genomic/epigenomic diversity and microenvironmental cues supply the substrates and pressures for plasticity from disease onset. This review anchors plasticity within normal lung development to clarify how fate programs are co-opted to drive progression, immune escape, therapy resistance, and invasion.

Oxidative stress is a pathological condition of redox signaling dysregulation and macromolecular oxidative damage arising from elevated ROS levels. Oxidative stress interacts with tumor cell growth regulation and tumor microenvironment remodeling, and has been a critical hallmark of cancer. Targeting oxidative stress has garnered great attention in cancer therapy development. However, it is still challenging due to the complexity and heterogeneity of oxidative stress regulation across different cancers, and this encourages a comprehensive understanding of the oxidative stress network in cancers to overcome this obstacle. Therefore, we introduced the oxidative stress generation and regulatory network within tumor cells and discussed their roles in both tumor cells and the tumor microenvironment. Subsequently, we summarized the current therapeutic strategies and highlighted emerging clinical applications, providing an up-to-date overview of oxidative stress-based approaches. Particularly, their cross-application with immunotherapy and nanomedicine has provided an excellent opportunity to integrate multiple effects, exhibiting surpassing advantages. This review elaborates on oxidative stress in cancer biology and its therapeutic implications. By integrating current knowledge and the emerging coordination with immunotherapy and nanomedicine, we underscore the potential of oxidative stress-targeting approaches. Future research on overcoming therapeutic resistance and developing compatible platforms to combine multiple approaches will pave the way to cancer elimination.

Immunosenescence, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the tumor microenvironment (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies-including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))-highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway senses cytosolic DNA and triggers innate immune responses. Pharmacological activation of the cGAS-STING pathway by cGAS-STING agonists to overcome cancer drug resistance offers substantial potential to promote antitumor immunity. However, small-molecule STING agonists show rapid excretion, low bioavailability, non-specificity, and adverse effects, which limit their therapeutic efficacy and in vivo applications. The recent emergence of nanomedicine has profoundly revolutionized STING agonist delivery, promoting tumor-targeted delivery and offering new opportunities for tumor-specific immunotherapy. A growing body of evidence has shown that cGAS-STING interacts with ferroptosis in cancer cells. Targeting the interplay between cGAS-STING and ferroptosis using nanomedicines offers a novel cancer treatment regimen. In this review, we outline the principal components of the cGAS-STING signaling cascade and discuss its role in cancer biology. We also review the role of the interplay between cGAS-STING and ferroptosis in cancer genesis. We then focus on providing an overview of the latest findings and emerging concepts that leverage the interplay between cGAS-STING and ferroptosis by nanomedicine to kill cancers. Finally, we discuss the key limitations of the current therapeutic paradigm and possible strategies to overcome them. This article highlights some promising therapeutic avenues that leverage the interplay of cGAS-STING and ferroptosis by nanomedicine, which could be used to treat cancer.

Circulating tumor cells (CTCs), which serve as an early indicator of tumors in peripheral blood, are closely associated with unfavorable prognoses in individuals with cancer. Gaining a thorough understanding of the heterogeneity and specific trajectory of CTCs during metastasis can yield valuable insights for the development of effective cancer treatment strategies. This review critically examines the contemporary knowledge of the in vivo process of CTCs, with a focus on the four key stages: dissemination, homing, colonization, and macro-metastasis. Each stage is discussed in terms of its associated characteristics, including epithelial-mesenchymal transition (EMT), dormancy, organotropism, and awakening. We also discuss recent advancements in CTC isolation, detection, cultivation and its potential applications. Additionally, it provides a comprehensive elucidation of the intricate mechanisms of immune evasion and drug resistance in CTCs, aiming to identify novel targets for cancer therapy. Finally, an overview of CTC interventions is presented, which may facilitate the development of personalized therapeutic approaches for patients and improve their metastasis-free prognostic outcomes.

Single-cell transcriptomics has significantly advanced our ability to uncover the cellular heterogeneity of tumors. A key challenge in single-cell transcriptomics is identifying cancer cells and, in particular, distinguishing them from non-malignant cells of the same cell lineage. Focusing on features that can be measured by single-cell transcriptomics, this review explores the molecular aberrations of cancer cells and their observable readouts at the RNA level. Identification of bona fide cancer cells typically relies on three main features, alone or in combination: i) expression of cell-of-origin marker genes; ii) inter-patient tumor heterogeneity; iii) inferred copy-number alterations. Depending on the cancer type, however, alternative or additional features may be necessary for accurate classification, such as single-nucleotide mutations, gene fusions, increased cell proliferation, and altered activation of signaling pathways. We summarize computational approaches commonly applied in single-cell analysis of tumoral samples, as well as less explored features that may aid the identification of malignant cells.

Ubiquitination, the prevalent posttranslational modification, plays a crucial role in regulating protein function, localization, and degradation within cellular environments. As an E3 ubiquitin ligase, TRIM65 has been shown in various studies to facilitate the ubiquitination of specific substrates, thereby controlling inflammation, innate immune responses, cell proliferation, apoptosis, and tumor progression. Given the multifaceted and significant role of TRIM65, this review compiles existing research on TRIM65 and lays the groundwork for future studies aimed at uncovering the mechanisms of TRIM65. Further understanding of TRIM65's interactions with its substrate proteins will offer valuable insights into the molecular underpinnings of certain diseases. Additionally, by identifying small molecules or inhibitors that target TRIM65, we may be able to develop novel drugs that modulate its activity. Such research could lead to more precise and effective treatments for conditions such as chronic inflammation, autoimmune diseases, and cancer. In summary, the study of TRIM65 not only enhances our understanding of fundamental cellular processes but also opens up new perspectives and avenues for the development of innovative therapies.

Breast cancer is a heterogeneous disease, which is still a challenge for modern cancer diagnostics. Despite significant progress in diagnosis, monitoring and treatment of breast cancer, it remains the leading cause of cancer-related death in women. Effective screening methods, which enable early diagnosis of the disease and rapid personalised treatment are crucial to improving survival of women with breast cancer. In recent years, increasing attention has been paid to the clinical utility of circulating biomarkers, such as proteins, autoantibodies, miRNAs, circRNAs, ctDNA or CTCs, which have the potential to supplement traditional methods of BC diagnosis. Despite much research, no sufficiently sensitive and minimally invasive marker has been identified to aid in the early diagnosis, monitoring of disease progression and response to therapy in women with breast cancer. Combinatorial analysis of circulating biomarkers is novel and promising approach, which may overcome the limitations of single biomarker assays.

Pancreatic cancer remains one of the most malignant tumors, characterized by limited treatment efficacy.

Combining immune checkpoint inhibitors (ICIs) and anti-angiogenic pharmacologic agents is an encouraging therapeutic approach in the treatment of non-small cell lung cancer (NSCLC). Currently, the only FDA-approved therapy combining an immune checkpoint inhibitor and a vascular endothelial growth factor (VEGF) inhibitor is atezolizumab, bevacizumab, and chemotherapy in first-line metastatic NSCLC patients. However, the combination of nivolumab, a programmed death-1 (PD-1) inhibitor, and bevacizumab has also shown encouraging results in patients with NSCLC with minimal adverse effects, respectively. This communication aims to highlight the efficacy of nivolumab and bevacizumab in NSCLC patients without sensitizing mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS proto-oncogene 1 (ROS1). In addition, the combination of nivolumab/atezolizumab and bevacizumab with other therapeutic agents is also discussed. We also underscore the adverse effects and limitations of such combinations in NSCLC patients. Future studies should focus on large-scale trials and biomarker identification to establish the benefits of these combination therapies in NSCLC patients.