Immune checkpoint inhibitors (ICIs) such as pembrolizumab have substantially improved outcomes in advanced non-small cell lung cancer (NSCLC), including squamous histology, but prolonged exposure may be complicated by immune-related adverse events (irAEs) and opportunistic infections. We report a 58-year-old man with advanced squamous NSCLC who achieved durable tumor control after six cycles of pembrolizumab plus platinum-based chemotherapy, followed by pembrolizumab maintenance monotherapy (18 cycles). During the later course, he developed severe bacterial pneumonia, invasive pulmonary aspergillosis (IPA), and subsequent aplastic anemia (AA)-like bone marrow failure. Despite systemic antifungal therapy and supportive measures, he experienced progressive pancytopenia complicated by massive hemoptysis and ultimately died. This case underscores the dual nature of ICIs: while providing meaningful and sustained antitumor benefit, they may rarely precipitate life-threatening hematologic toxicity and facilitate severe opportunistic infections in a complex immunologic milieu. Close surveillance of blood counts and infectious complications is warranted during long-term ICI therapy; unexplained cytopenias or new/worsening radiologic abnormalities should prompt early bone marrow evaluation and comprehensive microbiologic work-up. Metagenomic next-generation sequencing (mNGS) may offer useful adjunctive evidence in diagnostically challenging infections, particularly when invasive sampling is not feasible, but results should be interpreted in conjunction with clinical and radiologic context within a multidisciplinary framework.

Metastasis remains the major cause of mortality in colorectal cancer (CRC) despite continued advances in diagnosis and treatment. Increasing evidence identifies the CXCL12/CXCR4 chemokine axis as a critical driver of CRC progression and metastatic dissemination. Through dynamic interactions between tumor cells and the tumor microenvironment, this axis regulates multiple processes essential for metastasis, including driving migration and invasion, angiogenesis and lymphangiogenesis, and shaping the tumor immune microenvironment through recruitment of immunosuppressive populations, blockade of effector lymphocyte trafficking and function, and modulation of immunosuppressive cytokines including IL-10. In this review, we summarize the molecular mechanisms by which CXCL12/CXCR4 promotes CRC metastasis. These pleiotropic effects are mediated by crosstalk with PI3K/Akt, MAPK/ERK, and Wnt/β-catenin pathways, and are regulated at transcriptional, post-transcriptional, and post-translational levels. Preclinical studies demonstrate that CXCR4 antagonists (e.g., plerixafor, LY2510924) suppress metastasis and, when combined with immune checkpoint inhibitors, can reverse the "cold" immune phenotype of microsatellite-stable CRC. We also discuss recent advances in the regulation of CXCL12/CXCR4 expression, the role of related receptors such as CXCR7, and emerging strategies targeting this axis for therapeutic intervention. Collectively, current evidence supports the CXCL12/CXCR4 axis as a promising biomarker and therapeutic target in metastatic CRC, and further elucidation of its regulatory network may facilitate the development of more effective precision treatment strategies.

Antisynthetase syndrome (ASS) is a systemic autoimmune disorder classified as a subtype of the idiopathic inflammatory myopathies (IIM). The condition is defined by the presence of mutually exclusive autoantibodies directed against an aminoacyl-tRNA synthetase along with typical clinical manifestations, including myositis, Raynaud's phenomenon, arthritis, skin lesions such as mechanic hands, or interstitial lung disease (ILD). Anti-synthetase syndrome associated interstitial lung disease (ASS-ILD) can range from mild forms to rapidly progressive disease, which may lead to chronic pulmonary damage if misdiagnosed or inadequately treated. Patients with IIM carry an increased risk of developing neoplasms, most commonly adenocarcinoma, but not lymphoma or other hematologic malignancies. However, data on the association between ASS and malignancy remain very limited. We report the case of a patient with anti-PL-12 antisynthetase syndrome who subsequently developed NK/T-cell non-Hodgkin lymphoma, supplemented by a review of the pertinent literature.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by reinvigorating antitumor immunity through the blockade of inhibitory pathways such as programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Despite their remarkable clinical success, only a subset of patients derives durable benefit, whereas others exhibit primary or acquired resistance and develop immune-related adverse events (irAEs). These heterogeneous responses highlight an urgent need for robust biomarkers to predict therapeutic efficacy and for innovative combinatorial strategies to enhance clinical outcomes. Beyond their classical roles in hemostasis and thrombosis, platelets have recently emerged as pivotal modulators of tumor progression and immune regulation. Accumulating evidence indicates that platelets engage in dynamic crosstalk with tumor and immune cells, reshaping the tumor microenvironment (TME) and modulating the response to ICI therapy. Of note, platelet-associated immune checkpoint molecules (e.g., PD-L1) have shown great promise as liquid biopsy markers for patient stratification and real-time immunomonitoring. Furthermore, platelet-associated nucleic acids and traditional platelet parameters (such as platelet count and activation status) have been identified as accessible and effective biomarkers for predicting ICI responsiveness and irAEs. These platelet-derived components may also represent novel therapeutic targets to overcome resistance and potentiate ICI efficacy. Meanwhile, advances in biomaterials and genetic engineering have further enabled the development of platelet-based and platelet membrane (PM)-camouflaged delivery systems endowed with tumor-homing capacity, combinatorial drug delivery potential, and immune-responsive release properties. Collectively, these insights reposition platelets from passive participants to active regulators and versatile therapeutic platforms in cancer immunotherapy, providing a conceptual foundation for next-generation platelet-guided precision immunotherapeutic strategies.

This scoping review highlights the critical role of microRNAs (miRNAs) in mediating the bidirectional crosstalk between CD8+ T cells and tumor cells within the immunosuppressive tumor microenvironment (TME). Specific miRNAs (e.g., miR-155, miR-340-5p) orchestrate CD8+ T cell function by fine-tuning immune checkpoints (PD-1/PD-L1), metabolic reprogramming, and epigenetic states. Conversely, CD8+ T cells influence tumor behavior via exosomal miRNA transfer (e.g., miR-765). Our analysis reveals both pan-cancer mechanisms, such as PD-1/PD-L1 regulation, and tissue-specific miRNA functions (e.g., miR-143 in melanoma). To overcome translational challenges like off-target effects, innovative delivery strategies using lipid nanoparticles and engineered exosomes are being developed. This review provides a mechanistic framework for miRNA-mediated interactions, offers clinical insights for novel combination therapies, and assesses future directions, thereby advancing the development of precision immunotherapies.

Gynecological malignancies such as cancer of the cervix, ovary, endometrium, vulva, and vagina pose a severe global health burden. Although conventionally attributed to genetic mutation, hormonal imbalance, and chronic viral infection, including high-risk human papillomavirus, recent evidence suggests that the human microbiome plays a central role in their pathogenesis and development. This review summarizes existing evidence that microbial dysbiosis, specifically the depletion of beneficial Lactobacillus species and overrepresentation of anaerobic organisms such as Fusobacterium, Atopobium, and Sneathia, is implicated in carcinogenesis pathways. These include chronic inflammation, immune modulation, loss of epithelial barrier integrity, microbial metabolite toxicity, and estrogen metabolism by the estrobolome. Dysbiosis in the gut and reproductive tract has been associated with HPV persistence, tumor microenvironment remodeling, and immune surveillance/therapy resistance. Consequently, microbial signatures are being investigated as a potentially successful non-invasive biomarker for early diagnosis, prognosis, and monitoring of therapy in gynecological oncology. In addition, emergent microbiome-based therapies are being considered as potential adjunct therapies, including probiotics, prebiotics, dietary manipulation, vaginal microbiota transplantation, and fecal microbiota transplantation. This review connects the basic research microbiome research to translational and clinical practice, identifies associated limitations, and highlights how it may transform gynecological cancer prevention, detection, and treatment.

Glioblastoma (GBM) is a highly lethal malignancy driven by glioma-initiating cells (GICs). While GICs are known to profoundly remodel tumor microenvironment (TME) to promote progression and immune evasion within the vascular niche, the specific transcriptomic reprogramming and alternative splicing events driving their evolution from neural stem cells (NSCs), and how these intrinsic cellular state changes dictate multi-cellular immunosuppressive networks and checkpoints, remain poorly understood. Unraveling these complex tumor-vascular-immune interactions is critical for identifying novel vulnerabilities and developing effective immunotherapies.

To decode the GICs' evolutionary trajectory, we integrated RNA-seq and alternative splicing analysis of NSCs and patient-derived GIC cohorts. The malignant progression was mapped using scRNA-seq pseudotime analysis, and key targets were validated across clinical TCGA cohorts. Furthermore, we employed the large-scale single-cell foundation model, Geneformer, to perform in silico genetic perturbations, integrating it with interactome inference to decipher TME communication. Finally, the proposed tumor-endothelial-T cell multi-cellular axis was functionally validated utilizing in vitro tumor-HUVEC co-culture systems, qPCR, and FACS-based T cell activation (NFAT-Jurkat) assays.

Our multi-omics re-analysis identified extensive alternative splicing and transcriptional reprogramming during GICs evolution, pinpointing SLC1A3 as a core gene significantly upregulated along the malignant pseudotime trajectory and strongly correlated with poor clinical prognosis in GBM. AI-driven in silico virtual knockout utilizing Geneformer revealed that SLC1A3 acts as a master regulator of tumor network stability. Interactome analysis demonstrated that SLC1A3^hi tumor cells exhibit intensive communication with endothelial cells via specific ligand-receptor axes (e.g., TNC-ITGB1, PTN-SDC3). In vitro assays confirmed that endothelial cells were educated by SLC1A3^hi tumor cells that undergo malignant transition, drastically upregulating immune-suppressive factors, including CD274, TGFB1, IL10, and IDO1. Crucially, tumor-specific knockdown of SLC1A3 dismantled this vascular-immune suppressive niche, significantly restoring T cell activation in a multicellular co-culture model.

Our findings establish SLC1A3 not merely as an intrinsic driver of glioma development, but as a critical upstream node orchestrating a cascading tumor-endothelial-T cell immunosuppressive axis. By leveraging AI-based foundation models alongside robust biological validation, we uncovered a novel mechanism of vascular-mediated immune evasion, highlighting SLC1A3 as a highly promising therapeutic target to reprogram the glioblastoma microenvironment and restore anti-tumor immunity.

Tumor-infiltrating T cell receptor repertoires are increasingly profiled to assess intratumoral T cell dynamics and inform prognosis and treatment response. Most analyzes rely on aggregate diversity metrics, such as Shannon index or clonality, which describe overall repertoire structure but do not resolve changes in clonotype identity over time. Thus, intrinsic temporal dynamics of intratumoral T cell receptor repertoires during tumor progression remain incompletely defined.

In a bilateral murine cancer model, one tumor was surgically removed, and the paired tumor was collected 11 days later. The T cell receptor repertoires of these tumors, and of synchronously harvested bilateral tumors from separate control animals, were analyzed using diversity metrics, Morisita-Horn similarity, and clonal tracking approaches.

Time-matched bilateral tumors exhibited highly similar clonotype composition and abundance. In contrast, time-separated tumors showed reduced clonal overlap, increased fractions of private clonotypes, and redistribution of dominant clones. These changes occurred despite preserved global repertoire metrics, including clonotype number, Shannon diversity, and Gini coefficient.

Short-term tumor progression is associated with clear changes in the composition of the intratumoral T cell receptor repertoire, even when overall diversity appears stable. These results suggest that relying solely on global diversity metrics can obscure active clonal remodeling, underscoring the importance of monitoring individual T cell clonotypes to accurately capture intratumoral T cell dynamics over time.

Epstein-Barr virus (EBV) is associated with a wide spectrum of lymphoid and epithelial malignancies. This review provides a comprehensive pan-tumor perspective on the convergent oncogenic mechanisms, immune microenvironment characteristics, and shared therapeutic vulnerabilities across EBV-related cancers. We systematically summarize EBV infection and latency patterns, highlighting key shared signaling networks (e.g., NF-κB, PI3K/AKT) alongside nuanced immune evasion strategies, such as HLA modulation and steric immune blockade. By bridging these molecular insights with clinical translation, we evaluate emerging therapeutic paradigms, including immune checkpoint inhibitors, EBV-specific T-cell therapies, neutralizing antibodies, and mRNA vaccines. Ultimately, this synthesis underscores the potential of exploiting shared viral vulnerabilities to develop pan-tumor targeted therapies, offering a strategic roadmap for future clinical development.

Cancer immunotherapy has transformed oncology by harnessing the immune system to recognize and eliminate malignant cells. However, currently available options, including immune checkpoint inhibitors and cellular therapies, remain limited due to immune-related toxicities, high costs, off-target effects, and variable patient responses. These challenges highlight the need for alternative, synthetic immune-modulating strategies with improved precision, safety, and scalability. Aptamers have recently emerged as promising synthetic immune modulators. Owing to their chemical synthesis, small size, low immunogenicity, and extensive chemical tunability, aptamers offer distinct advantages over protein-based biologics, including enhanced tissue penetration, batch-to-batch consistency, and flexible pharmacokinetic optimization. Beyond their established diagnostic applications, aptamers are being applied as therapeutic agents capable of modulating immune checkpoints, cytokine signaling, and immune cell recruitment within the tumor microenvironment. Aptamer-drug conjugates (ApDCs) also represent a powerful extension of this technology, enabling targeted delivery of cytotoxic or immunostimulatory payloads to tumors while minimizing systemic toxicity. Through this review, we aim to provide a comprehensive overview of aptamer-based immunotherapies, encompassing molecular engineering strategies, SELEX optimization, and structural design principles that underpin target specificity and functional activity. We further examine preclinical and emerging clinical progress, translational challenges related to formulation, pharmacokinetics, and regulatory considerations, and the evolving role of ApDCs in cancer treatment. Finally, we discuss future perspectives for aptamer technologies as next-generation synthetic immune modulators, with the potential to complement or surpass conventional immunotherapeutic approaches in precision oncology.