Graft-versus-host disease (GVHD) remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT). Donor hematopoietic progenitor cells reconstitute the recipient's immune system after transplant, and newly generated donor-derived immune cells actively participate in propagating alloimmunity. Retinoic acid (RA) has well-known effects on the differentiation and proliferation of myeloid progenitor cells. We hypothesized that RA influences the reconstitution of some donor-derived myeloid cell populations after allogeneic HSCT. In a C57BL/6 into Balb/c murine allogeneic bone marrow transplantation (BMT) model, we found that Gr1+CD11b+CD84+F4-80- myeloid-derived suppressor cells (MDSCs) accumulated in the spleen of recipient mice early after BMT. Notably, the absolute number of MDSCs was significantly reduced in RA-treated mice compared with DMSO-treated mice. Furthermore, MDSCs isolated from RA-treated recipient mice showed decreased immunosuppressive function in mixed lymphocyte reactions (MLRs). Bulk RNA-sequencing (RNA-seq) revealed that RA treatment alters transcriptional programs involving Wnt signaling and the CCL2-CCR2 axis in MDSCs. We found that adding RA to the MDSC culture promotes the differentiation of Ly6C-Ly6G+ granulocytic MDSCs. Thus, enhancing RA signaling causes both quantitative and qualitative changes of MDSCs after allogeneic HSCT. Recent studies have demonstrated an important role of donor intestinal CD103+ dendrite cells (DCs) in propagating GVHD. We found that RA-treated recipient mice had significantly increased colonic CD103+ DCs compared with DMSO-treated mice. On the contrary, vitamin A deficiency was associated with a significant reduction in the percentage and absolute number of CD103+ DCs. To study the effects of RA on DCs in vitro, BM cells were cultured in the presence of GM-CSF. There was a significant increase in the percentage of CD11c+CD103+ mucosal DCs in cultures exposed to RA. Furthermore, RA-exposed DCs exhibited increased MHC-II expression and enhanced T-cell stimulatory capacity. In summary, our study demonstrated that RA participates in regulating donor MDSC and colonic CD103+ DC reconstitution after allogeneic HSCT. Therapeutic modulation of RA signaling or its downstream pathways may represent a strategy to limit alloimmunity and improve transplant outcomes.

Aging-related bone diseases are often interpreted through hormonal decline, defective remodeling, and chronic low-grade inflammation, yet these accounts do not fully capture the cellular, spatial, and temporal heterogeneity of skeletal aging. Bone is an immune-active organ sustained by coordinated signaling among skeletal, hematopoietic, immune, adipose, vascular, and neural compartments. Cellular senescence perturbs this network through stable cell-cycle arrest, metabolic remodeling, and a heterogeneous senescence-associated secretory phenotype (SASP). Whereas recent osteoimmunology syntheses broadly catalog age-related immune-bone interactions, our specific advance is to treat p16- and p21-associated states as functionally non-equivalent and to translate cell identity, anatomical compartment, persistence, and disease stage into explicit therapeutic decision points. We compare senescence programs in bone marrow stromal cells, osteoblast-lineage cells, osteocytes, osteoclast precursors, and immune populations, and then place them within an aging marrow ecosystem shaped by hematopoietic drift, marrow adiposity, vascular decline, and neural degeneration. These mechanisms are mapped across osteoporosis, osteoarthritis, rheumatoid arthritis, periodontitis, and delayed fracture healing. Emerging interventions include senolytics, senomorphics, immune-mediated clearance, bone-targeted delivery, and biomarker-guided patient selection. By operationalizing cell- and stage-resolved therapeutic windows, this framework aims to move senescence-targeted treatment beyond broad senolysis and toward testable precision strategies for aging bone.

Innate immune signaling is a central regulator of cancer immunity, but its effects are highly context-dependent. Acute and spatially controlled innate immune activation can promote dendritic-cell maturation, antigen presentation, and cytotoxic lymphocyte recruitment. In contrast, chronic, systemic, or therapy-induced inflammatory signaling often redirects the tumor ecosystem toward suppressive myeloid remodeling. This review discusses how innate immune pathways reshape myelopoiesis, macrophage polarization, MDSC activation, tumor-associated neutrophil recruitment, and stromal-myeloid inflammatory niches. We focus on selected signaling axes that represent distinct layers of innate inflammatory regulation, including cytokine-mediated myeloid instruction, inflammasome activation, nucleic-acid sensing, chemokine-driven recruitment, stromal transcriptional integration, and lipid-mediator signaling. These axes include IL-4/IL-4Rα, IL-1α/IL-1β, TGF-β, interferon signaling, NLRP3 inflammasome activation, STING, STAT3, IL-8/CXCR2, CCR2, and CysLTR1. These pathways can expand suppressive myeloid output from the bone marrow, reinforce tumor-associated macrophage states such as TREM2+, SPP1+, and NLRP3+ macrophages, and promote MDSC- and neutrophil-mediated resistance to immune checkpoint blockade. We also summarize tissue, spatial, and peripheral biomarkers that may identify myeloid-dominant immune resistance. Finally, we discuss therapeutic strategies aimed at blocking inflammatory drivers, inhibiting inflammasome-dependent amplification, preventing suppressive myeloid recruitment, and reprogramming established myeloid niches. Rather than cataloguing individual myeloid subsets or isolated inflammatory pathways, this review integrates systemic myelopoiesis, local TAM/MDSC/TAN remodeling, stromal-myeloid spatial niches, and therapy-induced inflammatory feedback into a unified framework for understanding and targeting immune checkpoint blockade resistance.

Cancer-associated fibroblasts (CAFs) are key regulators of tumor progression, immune modulation, and therapeutic resistance within the tumor microenvironment. Advances in single-cell and spatial profiling have revealed substantial heterogeneity among CAF populations, challenging the traditional view of CAFs as a uniformly tumor-promoting stromal population. Among the identified fibroblast states, antigen-presenting CAFs (apCAFs) represent a distinct subset characterized by major histocompatibility complex class II expression and the ability to directly interact with cluster of differentiation (CD) 4+ T cells. First described in pancreatic ductal adenocarcinoma, apCAFs have since been observed in multiple tumor types. Unlike professional antigen-presenting cells, apCAFs lack classical costimulatory molecules, suggesting that their antigen presentation leads to non-canonical immune outcomes, including immune modulation, immune tolerance, or regulatory T cell induction. Recent evidence indicates that apCAFs arise from multiple cellular sources, most prominently mesothelial cells undergoing mesothelial-to-mesenchymal transition in response to tumor-derived signals such as interleukin-1 and transforming growth factor-β. Additional studies have identified fibrocyte-like apCAFs derived from bone marrow-derived cells, underscoring the heterogeneous and context-dependent nature of this fibroblast state. Consistent with their antigen-presenting capacity, apCAFs localize to immune-enriched niches, including tertiary lymphoid structures, where they influence local immune architecture and T cell functional states. Notably, apCAFs have been linked to both tumor-promoting and tumor-restraining activities, highlighting their dual roles in cancer immunity. Importantly, these immunological functions have direct clinical implications: apCAF-enriched stromal programs are associated with distinct immune landscapes and may influence responses to immune checkpoint blockade. This review summarizes current knowledge of the biology of apCAFs, with emphasis on their defining molecular features, cellular origins, immunological functions, and clinical relevance. Therefore, defining the context-dependent roles of apCAFs will be essential for designing next-generation stromal-targeted and immunotherapy-combination strategies that selectively enhance antitumor immunity while limiting tumor-promoting fibroblast functions.

Osteoimmunology represents an emerging interdisciplinary domain that investigates the reciprocal crosstalk between the skeletal and immune compartments, which serves as the core immunological basis for the pathogenesis of diverse musculoskeletal disorders. This bidirectional communication is facilitated by a shared microenvironment and common molecular mediators. This review systematically synthesizes the regulatory effects of T cells, B cells, and macrophages on bone homeostasis. Their modulatory actions are predominantly executed via proinflammatory cytokines and canonical signaling cascades, with particular emphasis on the RANKL/RANK/OPG axis. In parallel, we highlight that bone lineage cells (e.g., osteoblasts and osteoclasts) are not merely passive targets of immune regulation. Instead, they actively participate in immune cell development and function by secreting cytokines. Together, these interactions form an integrated and dynamic regulatory balance. Under physiological conditions, this finely tuned bone-immune crosstalk maintains bone-immune homeostasis. Its disruption, however, contributes to the pathogenesis of typical musculoskeletal pathologies, including rheumatoid arthritis, osteoporosis, and tumor-associated bone metastasis. Adopting an integrated perspective, this review integrates the shared regulatory mechanisms and microenvironment-dependent features of osteoimmune interactions. It provides a theoretical framework for understanding osteoimmune imbalance in musculoskeletal disorders and for developing precise therapeutic strategies.

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions are rare aggressive malignancies. FGFR1-rearranged cases are particularly high-risk. Among FGFR1 fusion partners, TIF1/TRIM24::FGFR1 is exceptionally rare. We report a 33-year-old woman presenting with fever, skin bruising, leukocytosis, thrombocytopenia, and circulating blasts. Bone marrow and flow cytometry identified abnormal B-lymphoblasts, myeloid blasts, and monocytic populations, supporting a mixed-phenotype acute leukemia presentation. Cytogenetics detected t(8;7)(p11;q34) translocation. Whole-transcriptome sequencing identified a TIF1/TRIM24::FGFR1 fusion transcript, confirmed by Sanger sequencing and FISH. RUNX1 missense mutation was also detected. The patient achieved complete remission after induction chemotherapy. However, after discontinuation of therapy and refusal of allo-HSCT, she relapsed rapidly with clonal evolution. A second remission was transient, and the patient died of cerebral hemorrhage. This case highlights the aggressive biology of TIF1/TRIM24::FGFR1-rearranged MLN-TK, the limitation of conventional chemotherapy, and the potential value of fusion-specific monitoring. Early allo-HSCT should be considered once remission is achieved, and FGFR1-directed therapy may represent a potential option in selected patients. However, clinical evidence remains limited and further studies are required.

The complete blood count (CBC) is one of the most frequently used laboratory tests in clinical practice and is often the first abnormal finding that prompts further evaluation. However, its interpretation is often limited to identifying values outside reference ranges, which may lead to both overinterpretation of minor abnormalities and under-recognition of serious disease. The CBC provides a rapid and integrated reflection of hematopoiesis and systemic physiology. Subtle combinations of abnormalities across multiple cell lineages, discordance between indices, and inappropriate marrow responses may represent early clues to conditions such as bone marrow failure, hemolysis, severe infection, and hematologic malignancy. In this review, we propose a practical, physiology-based framework for CBC interpretation designed for general physicians. This emphasizes simultaneous assessment of the three hematopoietic lineages, integration of key parameters, including reticulocyte count and cell size variability, and interpretation based on underlying pathophysiologic processes, including production, destruction or consumption, distribution, and reactive changes. In addition, we highlight common pitfalls related to spurious results and analyzer limitations and outline clinically important red flag patterns that require urgent evaluation. By applying this structured, physiology-based approach, clinicians can use the CBC more effectively to guide diagnostic reasoning, prioritize further investigations, and identify patients who require timely intervention. The CBC should therefore be used not merely as a screening test, but as a practical tool for clinical decision-making in daily practice.

A significant challenge in the study of neuroimmune responses is the identification and separation of resident microglia from infiltrating bone marrow-derived macrophages. Therefore, we investigated whether dual labelling of Cx3cr1 and Ccr2 is sufficient to discriminate retinal microglia from infiltrating macrophages in mice that develop spontaneous autoimmune uveoretinitis-a condition dependent on infiltration of lymphocytes and antigen presenting cells from the circulation into the retina. Mice expressing red fluorescent protein (RFP) under control of the Ccr2 promoter and green fluorescent protein (GFP) under control of the Cx3cr1 promoter (Ccr2RFPCx3cr1GFP mice) were crossed with the uveitogenic R161H mouse line. Retinas of R161Hneg x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice, including those given an optic nerve crush injury to stimulate retinal MG expansion, and R161H+/- x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice were analyzed for RFP and GFP expressing cells by fundoscopy, flow cytometry, fluorescence microscopy, and for Ccr2 expression by single cell RNA sequencing of retinal CD45+ cells. Retinas from control and optic nerve crushed R161Hneg x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice contained a single population of CD45+ cells expressing a uniquely high level of GFP but were devoid of RFP+ cells, while retinas from R161H+/- x Ccr2RFP+/-Cx3cr1GFP+/- F1 mice had GFPhi cells and increasing amounts of GFPnegRFP+ and GFPlo-medRFP+ cells as uveoretinitis progressed. Thus, dual labelling of Ccr2 and Cx3cr1 can distinguish retinal microglia from infiltrating immune cells, and as GFP+, RFP+, and GFP+RFP+ cells can be easily separated by flow cytometry, our system provides a method for their separation for downstream cellular analysis.

SRSF2 mutations occur in 5-15% of acute myeloid leukemia (AML) and ~15% of myelodysplastic neoplasms (MDS), are enriched in elderly/secondary AML, and lack mutation-directed therapy. We aimed to identify vulnerabilities in MDS/AML with SRSF2 mutations. Ex vivo drug-sensitivity testing of bone marrow cells from AML patients and controls showed that SRSF2-mutant cells are sensitive to CHK1 and WEE1 inhibitors. To test causality, we engineered isogenic K562 cell line clones expressing SRSF2P95H/L/R mutations. RNA sequencing confirmed splicing aberrations characteristic of MDS/AML in these clones. We found that SRSF2P95H/L/R sensitizes cells to ATR-CHK1-WEE1 inhibition. Bone marrow progenitors from Srsf2P95H knock-in mice showed heightened sensitivity to CHK1 inhibition, corroborating the human SRSF2-mutant data. U2af1S34F knock-in mouse progenitors extended this vulnerability to another spliceosome-mutant context. In contrast, RUNX1 mutations were linked to resistance to CHK1 and WEE1 inhibition in SRSF2-mutant AML samples. Runx1 disruption also caused resistance to CHK1 inhibitors in knock-in mouse progenitors harboring Srsf2P95H or U2af1S34F, indicating that RUNX1 loss of function is a mechanism of resistance. In conclusion, SRSF2 and U2AF1 mutations are biomarkers of sensitivity to ATR-CHK1 pathway inhibitors, while RUNX1 mutations cause resistance in splicing factor-mutant cells. These biomarkers can support patient stratification in MDS/AML.