Bone metastasis is the major cause of death in breast cancer. The lack of effective treatment suggests that disease mechanisms are still largely unknown. As a key component of the tumor microenvironment, macrophages promote tumor progression and metastasis. In this study, we found that macrophages are abundant in human and mouse breast cancer bone metastases. Macrophage ablation significantly inhibited bone metastasis growth. Lineage tracking experiments indicated that these macrophages largely derive from Ly6C+CCR2+ inflammatory monocytes. Ablation of the chemokine receptor, CCR2, significantly inhibited bone metastasis outgrowth and prolonged survival. Immunophenotyping identified that bone metastasis–associated macrophages express high levels of CD204 and IL4R. Furthermore, monocyte/macrophage-restricted IL4R ablation significantly inhibited bone metastasis growth, and IL4R null mutant monocytes failed to promote bone metastasis outgrowth. Together, this study identified a subset of monocyte-derived macrophages that promote breast cancer bone metastasis in an IL4R-dependent manner. This suggests that IL4R and macrophage inhibition can have potential therapeutic benefit against breast cancer bone disease.

Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.

Background: The difficulty of assessment of neoadjuvant chemotherapeutic response preoperatively may hinder personalized-medicine strategies that depend on the results from pathological examination. Methods: A total of 191 patients with high-grade osteosarcoma (HOS) were enrolled retrospectively from November 2013 to November 2017 and received neoadjuvant chemotherapy (NCT). A cutoff time of November 2016 was used to divide the training set and validation set. All patients underwent diagnostic CTs before and after chemotherapy. By quantifying the tumor regions on the CT images before and after NCT, 540 delta-radiomic features were calculated. The interclass correlation coefficients for segmentations of inter/intra-observers and feature pair-wise correlation coefficients (Pearson) were used for robust feature selection. A delta-radiomics signature was constructed using the lasso algorithm based on the training set. Radiomics signatures built from single-phase CT were constructed for comparison purpose. A radiomics nomogram was then developed from the multivariate logistic regression model by combining independent clinical factors and the delta-radiomics signature. The prediction performance was assessed using area under the ROC curve (AUC), calibration curves and decision curve analysis (DCA). Results: The delta-radiomics signature showed higher AUC than single-CT based radiomics signatures in both training and validation cohorts. The delta-radiomics signature, consisting of 8 selected features, showed significant differences between the pathologic good response (pGR) (necrosis fraction ≥90%) group and the non-pGR (necrosis fraction < 90%) group (P < 0.0001, in both training and validation sets). The delta-radiomics nomogram, which consisted of the delta-radiomics signature and new pulmonary metastasis during chemotherapy showed good calibration and great discrimination capacity with AUC 0.871 (95% CI, 0.804 to 0.923) in the training cohort, and 0.843 (95% CI, 0.718 to 0.927) in the validation cohort. The DCA confirmed the clinical utility of the radiomics model. Conclusion: The delta-radiomics nomogram incorporating the radiomics signature and clinical factors in this study could be used for individualized pathologic response evaluation after chemotherapy preoperatively and help tailor appropriate chemotherapy and further treatment plans.

Extracellular vesicles (EVs) are transport vesicles secreted by living cells and released into the extracellular environment. Recent studies have shown that EVs serve as “messengers” in intercellular and inter‐organismal communication, in both normal and pathological processes. EVs, as natural nanocarriers, can deliver bioactivators in therapy with their endogenous transport properties. This review article describes the engineering EVs of sources, isolation method, cargo loading, boosting approach, and adjustable targeting of EVs. Furthermore, the review summarizes the recent progress made in EV‐based delivery systems applications, including cancer, cardiovascular diseases, liver, kidney, nervous system diseases, and COVID‐19 and emphasizes the obstacles and challenges of EV‐based therapies and possible strategies.

Metal ions have been identified as important bone metabolism regulators and widely used in the field of bone tissue engineering, however their exact role during bone regeneration remains unclear. Herein, the aim of study was to comprehensively explore the interactions between osteoinductive and osteo-immunomodulatory properties of these metal ions. In particular, the osteoinductive role of zinc ions (Zn²⁺), as well as its interactions with local immune microenvironment during bone healing process, was investigated in this study using a sustained Zn²⁺ delivery system incorporating Zn²⁺ into β-tricalcium phosphate/poly(L-lactic acid) (TCP/PLLA) scaffolds. The presence of Zn²⁺ largely enhanced osteogenic differentiation of periosteum-derived progenitor cells (PDPCs), which was coincident with increased transition from M1 to M2 macrophages (M $$\varphi $$φ s). We further confirmed that induction of M2 polarization by Zn²⁺ was realized via PI3K/Akt/mTOR pathway, whereas marker molecules on this pathway were strictly regulated by the addition of Zn²⁺. Synergically, this favorable immunomodulatory effect of Zn²⁺ further improved the osteogenic differentiation of PDPCs induced by Zn²⁺ in vitro. Consistently, the spontaneous osteogenesis and pro-healing osteoimmunomodulation of the scaffolds were thoroughly identified in vivo using a rat air pouch model and a calvarial critical-size defect model. Taken together, Zn²⁺-releasing bioactive ceramics could be ideal scaffolds in bone tissue engineering due to their reciprocal interactions between osteoinductive and immunomodulatory characteristics. Clarification of this synergic role of Zn²⁺ during osteogenesis could pave the way to develop more sophisticated metal-ion based orthopedic therapeutic strategies.

The poor 5-year survival rate in high-grade osteosarcoma (HOS) has not been increased significantly over the past 30 years. This work aimed to develop a radiomics nomogram for survival prediction at the time of diagnosis in HOS. In this retrospective study, an initial cohort of 102 HOS patients, diagnosed from January 2008 to March 2011, was used as the training cohort. Radiomics features were extracted from the pretreatment diagnostic computed tomography images. A radiomics signature was constructed with the lasso algorithm; then, a radiomics score was calculated to reflect survival probability by using the radiomics signature for each patient. A radiomics nomogram was developed by incorporating the radiomics score and clinical factors. A clinical model was constructed by using clinical factors only. The models were validated in an independent cohort comprising 48 patients diagnosed from April 2011 to April 2012. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. Kaplan-Meier survival analysis was performed. The radiomics nomogram showed better calibration and classification capacity than the clinical model with AUC 0.86 vs. 0.79 for the training cohort, and 0.84 vs. 0.73 for the validation cohort. Decision curve analysis demonstrated the clinical usefulness of the radiomics nomogram. A significant difference (p-value <.05; log-rank test) was observed between the survival curves of the nomogram-predicted survival and non-survival groups. The radiomics nomogram may assist clinicians in tailoring appropriate therapy.