Stimulating efferocytosis, the phagocytic removal of apoptotic cells by macrophages, has been proposed as a method to eliminate dying or dead cells that accumulate and contribute to diseases such as cancer, atherosclerosis, and infection. Toxicity related to the off-target clearance of healthy tissue has led to the premature termination of multiple clinical programs for proefferocytic therapies. To identify potential proefferocytic therapies with established risk profiles, we screened ~3000 US Food and Drug Administration (FDA)-approved drugs and other well-characterized compounds for their capacity to stimulate efferocytosis. We found that the antipsychotic drug thiothixene stimulated efferocytosis of apoptotic and lipid-laden cells by mouse and human macrophages and enhanced the continual efferocytosis of apoptotic cells. Consistent with thiothixene's suppressive effects on dopaminergic signaling, dopamine potently inhibited efferocytosis in a manner that was only partially reversed by thiothixene. The prophagocytic effects of thiothixene in mouse macrophages depended on increased expression of the gene encoding the retinol-binding protein receptor Stra6L, which, in turn, promoted the production of the continual efferocytosis stimulator arginase 1. Our findings demonstrate that dopamine inhibits efferocytosis in macrophages and identify thiothixene, a generic, FDA-approved antipsychotic drug that has been in use for more than 50 years, as a promising candidate for promoting continual efferocytosis and the removal of diseased tissue.

Patients with osteosarcoma (OS) exhibit metastasis upon diagnosis, and the condition frequently acquires resistance to traditional chemotherapy treatments, failing the therapy. The objective of this research was to examine the impact of curculigoside (Cur), a key phenolic compound discovered in the rhizome of C. orchioides Gaertn, on OS cells and the surrounding tumor environment.

We assessed the impact of curculigoside on tumor inhibition in four osteosarcoma cell lines and mice tumor xenograft models using various techniques including cell viability assay, wound healing assay, cell apoptosis analysis, immunofluorescent staining, and IHC. Moreover, we created a mini-PDX model by utilizing freshly obtained primary OS cells from surgically removed OS tissues to evaluate the possible clinical use of Cur.

The results of our study show that Cur triggers cell death in OS cells and enhances the maturation of RAW264.7 cells. By effectively inhibiting the growth of OS cells, these actions mechanistically trigger the catastrophic buildup of unbound iron and uncontrolled lipid peroxidation, ultimately resulting in ferroptosis. Moreover, additional validation of Cur's substantial antineoplastic impact is obtained through in vivo experiments employing xenograft and mini-PDX models.

To sum up, this research is the initial one to exhibit the anti-tumor effects of Cur on OS using various methods, indicating that Cur shows potential as a viable approach for treating OS.

Osteosarcoma (OS) is the most common primary bone malignancy, with OS lung metastasis (OSLM) being the leading cause of death in OS patients. No curative pharmacotherapies for OSLM are available, highlighting the clinical need for new therapies. Improved and rigorous preclinical models of OSLM are key in supporting advancements in this field. We aimed to develop an immunocompetent mouse model of OSLM that allows monitoring pharmacotherapies' effect on the lung metastatic burden over time and assessing the impact of sex as a biological variable in tumor growth and response to therapy. We transformed K7M2 cells to express bioluminescence and fluorescence, enabling real-time tracking of OSLM in BALB/c mice following tail vein injection. Metastasis was confined to the lungs and exhibited exponential growth with typical downregulated Fas receptor expression. In vivo bioluminescence correlated strongly with ex vivo, suggesting its reliability for evaluating metastatic progression and therapy response. Fluorescence from tdT was stable upon tissue processing, providing unique opportunities to probe the tumor characteristics ex vivo. We also assessed the effect of local lung-delivered gemcitabine, which was well-tolerated and significantly reduced OSLM burden without causing pulmonary toxicity. However, treatment did not resolve metastatic disease. We also explored the effect of sex on tumor growth and response to therapy; while no difference was observed in tumor growth between male and female mice, females showed a better response to local gemcitabine administration. In sum, we established a robust and rigorous immunocompetent mouse model of OSLM that will facilitate exploring new pharmacotherapies for OSLM.

Osteosarcoma, a primary malignant bone tumor commonly found in adolescents, is highly aggressive, with a high rate of disability and mortality. It has a profound negative impact on both the physical and psychological well-being of patients. The standard treatment approach, comprising surgery and chemotherapy, has seen little improvement in patient outcomes over the past several decades. Once relapse or metastasis occurs, prognosis worsens significantly. Therefore, there is an urgent need to explore new therapeutic approaches. In recent years, the successful application of immunotherapy in certain cancers has demonstrated its potential in the field of cancer treatment. Macrophages are the predominant components of the immune microenvironment in osteosarcoma and represent critical targets for immunotherapy. Macrophages exhibit dual characteristics; while they play a key role in maintaining tumor-promoting properties within the microenvironment, such as inflammation, angiogenesis, and immune suppression, they also possess antitumor potential as part of the innate immune system. A deeper understanding of macrophages and their relationship with osteosarcoma is essential for the development of novel therapeutic strategies.

Osteosarcoma (OS) is a commonly observed malignant tumor in orthopedics that has a very poor prognosis. The endosomal sorting complex required for transport (ESCRT) is important for the development and progression of cancer and may be a significant target for cancer therapy. First, we built a prognostic signature using 7 ESCRT-related genes (ERGs) to predict OS patient prognosis. Analysis of internal and external datasets revealed that the ERG signature has good predictive ability and reproducibility. Immune analysis demonstrated a significant correlation between OS patient immune status and ERG signature score. Moreover, ERG signature score was found to be associated with the response of OS patients to immunotherapy and anticancer drugs. Additionally, we constructed a prognostic signature consisting of 10 ESCRT-related long noncoding RNAs (ERLs) that effectively predicted the prognosis of OS patients. Furthermore, two subgroups of OS patients with distinct prognoses (clusters 1 and 2) were identified. Finally, LMO7-AS1 was chosen for functional experimental validation. The knockdown of LMO7-AS1 suppressed the malignant progression of OS cells. Furthermore, transcriptome sequencing was performed on OS cells and revealed a correlation between LMO7-AS1 and the PI3K-Akt signaling pathway. In conclusion, our ESCRT transcriptome-associated signatures can act as prognostic biomarkers for OS, and LMO7-AS1 is a novel therapeutic target for the treatment of OS.

Osteosarcoma is a highly malignant tumor with unsatisfactory therapeutic outcomes achieved by chemotherapy, radiotherapy, and surgery. As an emerging oncological treatment, immunotherapy has shown potential in the clinical management of many tumors but has a poor response rate in osteosarcoma. The immunosuppressive microenvironment in osteosarcoma is the main reason for the ineffectiveness of immunotherapy, in which the low immune response rate of immune effector cells and the high activation of immunosuppressive cells contribute to this outcome. Therefore, modulating the function of the immune microenvironment in osteosarcoma is expected to remodel the immunosuppressive microenvironment of osteosarcoma and enhance the efficacy of immunotherapy. This article reviews the role of immune cells in the progression of osteosarcoma, describes the corresponding regulatory tools for the characteristics of different cells to enhance the efficacy of osteosarcoma immunotherapy, and concludes the prospects and future challenges of osteosarcoma immunotherapy.

Pediatric osteosarcoma, the most prevalent primary malignant bone tumor in children, is marked by aggressive progression and a generally poor prognosis. Despite advances in treatment, including multi-agent chemotherapy, survival rates remain suboptimal, with metastasis, particularly to the lungs, contributing significantly to mortality. The tumor microenvironment plays a crucial role in osteosarcoma progression, with immune cells such as tumor-associated macrophages and T lymphocytes significantly influencing tumor behavior. The immunosuppressive environment, dominated by M2 macrophages, contributes to immune evasion and poor therapeutic outcomes, though recent findings suggest the potential for reprogramming these cells to enhance immune responses. This review provides a comprehensive overview of the immune landscape in pediatric osteosarcoma, with a focus on the role of immune cells and their interactions within the tumor microenvironment (TME). It examines the impact of immune checkpoints, genetic mutations, and inflammatory pathways on osteosarcoma progression, highlighting their contribution to tumor immune evasion and disease advancement. Additionally, emerging immunotherapeutic strategies, such as immune checkpoint inhibitors, macrophage reprogramming, and antibody-based therapies, are summarized in detail, showcasing their potential to improve therapeutic outcomes.

Osteosarcoma is one of the most common malignant bone tumours in children. In this study, we aimed to construct a cuproptosis-related lncRNAs signature to predict the prognosis and immune landscape of osteosarcoma patients. Databases from TARGET were used to acquire osteosarcoma patient datasets, which included clinical information and RNA sequencing data. Cuproptosis-related lncRNAs was obtained by correlation analysis. Through univariate Cox regression analysis, prognosis-related lncRNAs were obtained. We used nonnegative matrix factorization clustering to identify potential molecular subgroups with different cuproptosis-related lncRNA expression patterns. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression analysis were used to construct the prognostic signature. The ESTIMATE algorithm, Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes were applied to explore the underlying mechanisms in the immune landscape of osteosarcoma. We used gene set enrichment analysis to compare the different enrichments in the high-risk group and the low-risk group. Furthermore, we predicted the response to targeted drugs in patients with different risk groups. Using multivariable analysis, we developed a risk scoring model based on 7 long noncoding RNAs and calculated two molecular subgroups from osteosarcoma patients from the database. There is a better immune microenvironment in the low-risk group compared to the high-risk group. At the same time, the gene functional enrichment analysis based on the differently expressed genes obtained by grouping showed they were mainly related to immunity, indicating that cuproptosis-related lncRNAs may affect the prognosis of osteosarcoma by regulating immunity. Moreover, these patients in high-risk group were more susceptible to targeted drugs than the low-risk group. We identified a cuproptosis-related lncRNA prognostic signature for osteosarcoma and showed a close connection in terms of immunity. Moreover, we provided some potential targeted drugs for the treatment of osteosarcoma.

Lung metastasis has garnered significant attention due to its prevalent occurrence. Pre-metastatic niche (PMN) establishment is a critical prerequisite for the onset of lung metastasis. Emerging evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles in the metastatic cascade to the lungs. However, the relationship between lncRNA expression profiles and the formation of PMN remains uncharacterized. This study aims to explore the expression profiles and potential roles of lncRNAs in the context of pre-metastatic lung microenvironment.

RNA sequencing was utilized to elucidate the lncRNA landscape in pre-metastatic lung of murine models. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to infer the prospective functions of the differentially expressed lncRNAs. Among these, lncRNA Gm5144-202 in alveolar macrophages (AMs) was further scrutinized for its role in driving M2 macrophage polarization, facilitating the formation of PMN, and orchestrating the apoptosis, proliferation, and migration of tumor cells in vitro.

A total of 232 lncRNAs exhibited differential expression in pre-metastatic murine lungs compared to normal controls, predominantly enriching pathways such as PI3K-Akt signaling, calcium signaling, neuroactive ligand-receptor interaction, and NF-κB signaling. Notably, lncRNA Gm5144-202 exhibited the most pronounced difference, with elevated level in alveolar macrophages (AMs) during the pre-metastatic phase. Silencing of lncRNA Gm5144-202 impeded the polarization of M2-like macrophages, suppressed the expression of factors critical for the formation of the PMN, and inhibited tumor cell invasion.

Our research delineated the lncRNA expression profiles in pre-metastatic pulmonary tissues and identified, for the first time, the pivotal role of lncRNA Gm5144-202 in modulating M2 macrophage polarization and tumor cell invasiveness. Consequently, targeting lncRNA Gm5144-202 holds substantial promise for translational applications aimed at mitigating pulmonary metastasis.

The RON receptor tyrosine kinase is critical in the pathogenesis of various cancer types, however, its role in bladder cancer invasive growth is still largely unknown. Here, we found that over 90% of bladder cancer samples exhibit elevated levels of RON expression, with significantly higher expression levels observed in invasive bladder cancer compared to non-invasive bladder cancer. In vitro, RON activation resulted in increased bladder cancer cell migration and invasiveness. Results from mRNA sequencing and transcriptome analysis further demonstrated that MMP12, a downstream molecule of RON, is functionally involved in regulating RON-mediated bladder cancer cell migration and invasiveness. The underlying mechanism appeared to be the RON-mediated inhibition of HIF-2α ubiquitination, which is channeled through the activation of the JNK signaling pathway. Consequently, the activated JNK pathway increased MMP12 expression, ultimately driving bladder cancer cell migration and invasion. As evident in bioinformatics and dual-luciferase reporter assays, the RON mRNA at its 3'-untranslated regions specifically interacted with hsa-miR-659-3p. The binding of hsa-miR-659-3p downregulated the RON gene expression, attenuating the receptor-mediated tumorigenic activities of bladder cancer cells in vitro and in vivo. In conclusion, aberrant RON expression in bladder cancer cells and MMP12 and HIF-2α activities form a functional axis that causes increased bladder cancer cell migration and invasion. The fact that hsa-miR-659-3p downregulates RON expression indicates its critical role in attenuating RON-mediated tumorigenic effect on bladder cancer cells. These findings highlight the importance of RON targeting as a therapeutic means for potential bladder cancer therapy.

Osteosarcoma, a highly aggressive malignant bone tumor, is significantly influenced by the intricate interactions within its tumor microenvironment (TME), particularly involving neutrophils. This review delineates the multifaceted roles of neutrophils, including tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs), in osteosarcoma's pathogenesis. TANs exhibit both pro- and anti-tumor phenotypes, modulating tumor growth and immune evasion, while NETs facilitate tumor cell adhesion, migration, and immunosuppression. Clinically, neutrophil-related markers such as the neutrophil-to-lymphocyte ratio (NLR) predict patient outcomes, highlighting the potential for neutrophil-targeted therapies. Unraveling these complex interactions is crucial for developing novel treatment strategies that harness the TME to improve osteosarcoma management.

In this work, we review the multifaceted connections between osteosarcoma (OS) biology and normal bone development. We summarize and critically analyze existing research, highlighting key areas that merit further exploration. The review addresses several topics in OS biology and their interplay with normal bone development processes, including OS cell of origin, genomics, tumor microenvironment, and metastasis. We examine the potential cellular origins of OS and how their roles in normal bone growth may contribute to OS pathogenesis. We survey the genomic landscape of OS, highlighting the developmental roles of genes frequently altered in OS. We then discuss the OS microenvironment, emphasizing the transformation of the bone niche in OS to facilitate tumor growth and metastasis. The role of stromal and immune cells is examined, including their impact on tumor progression and therapeutic response. We further provide insights into potential development-informed opportunities for novel therapeutic strategies.

Despite recent advances in clinical treatments, identifying high-risk osteosarcoma (OS) patients remains an unresolved clinical challenge. Mitophagy, a specialized form of cellular autophagy, selectively reduces the number of mitochondria or repairs their abnormal functions in response to external stress, thereby ensuring mitochondrial quality and maintaining mitochondrial function. Mitophagy plays a crucial role in cancer development, including processes such as mitochondrial repair, homeostasis maintenance, and tumor metabolism. However, its impact on OS has not yet been reported. In this study, we collected 58 mitophagy-related genes (MPRGs) from the TARGET and GEO databases and bioinformatically screened for those associated with OS prognosis. By LASSO-multivariable Cox regression algorithm, we subsequently developed a novel scoring system, the MPRG score, and validated its significance in predicting OS prognosis. Immune landscape analysis showed patients in the low MPRG group had a higher immune infiltration level than those in the high MPRG group. Drug sensitivity differences highlighted the potential need for alternative therapeutic strategies based on MPRG scoring system. The distribution characteristics of the MPRG signature in different cell subtypes of OS were explored by single-cell sequencing analyses. In vitro experiments further confirmed the abnormal expression of screened targets in OS. Our findings highlight the role of mitophagy in OS and its potential as a therapeutic target.

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages.

Accumulating evidence demonstrates that an increased tumor-associated macrophage abundance is often associated with poor prognosis in colorectal cancer (CRC). The mechanism underlying the effect of tumor-derived exosomes on M2 macrophage polarization remains elusive.

The novel circular RNA circPOLQ exhibited significantly higher expression in CRC tissues than in paired normal tissues. Higher circPOLQ expression was associated with poorer prognosis in patients with CRC. In vitro and in vivo experiments showed that tumor-derived exosomal circPOLQ did not directly regulate CRC cell development but promoted CRC metastatic nodule formation by enhancing M2 macrophage polarization. circPOLQ activated the interleukin-10/signal transducer and activator of transcription 3 axis by targeting miR-379-3 p to promote M2 macrophage polarization.

circPOLQ can enter macrophages via CRC cell-derived exosomes and promote CRC metastatic nodule formation by enhancing M2 macrophage polarization. These findings reveal a tumor-derived exosome-mediated tumor-macrophage interaction potentially affecting CRC metastatic nodule formation.

Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an in situ injectable hydrogel, termed MPB-NO@DOX + ATRA gel, which was locally formed within the tumor resection cavity. The MPB-NO@DOX + ATRA gel was fabricated by mixing a thrombin solution, a fibrinogen solution containing all-trans retinoic acid (ATRA), and a Mn/NO-based immune nano-activator termed MPB-NO@DOX. ATRA promoted the differentiation of cancer stem cells, inhibited cancer cell migration, and affected the polarization of tumor-associated macrophages. The outer MnO2 shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn2+ and produce O2, resulting in the release of doxorubicin (DOX). The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn2+ to activate the cGAS-STING pathway and stimulate an anti-tumor immune response. In addition, when MPB-NO@DOX was exposed to 808 nm laser irradiation, the Fe-NO bond was broken to release NO, which downregulated the expression of PD-L1 on the surface of tumor cells and reversed the immunosuppressive tumor microenvironment. In conclusion, the MPB-NO@DOX + ATRA gel exhibited excellent anti-tumor efficacy. The results of this study demonstrated the great potential of in situ injectable hydrogels in preventing postoperative tumor recurrence.

Exosomes are vesicles with a lipid bilayer structure that carry various active substances, such as proteins, DNA, non-coding RNA, and nucleic acids; these participate in the immune response, tissue formation, and cell communication. Owing to their low immunogenicity, exosomes play a key role in regulating the skeletal immune environment. Macrophages are important immune cells that swallow various cellular and tissue fragments. M1-like and M2-like macrophages differentiate to play pro-inflammatory, anti-inflammatory, and repair roles following stimulation. In recent years, the increase in the population base and the aging of the population have led to a gradual rise in orthopedic diseases, placing a heavy burden on the social medical system and making it urgent to find effective solutions. Macrophages and their exosomes have been demonstrated to be closely associated with the pathogenesis and prognosis of orthopedic diseases. An in-depth understanding of their mechanisms of action and the interaction between them will be helpful for the future clinical treatment of orthopedic diseases. This review focuses on the mechanisms of action, diagnosis, and treatment of orthopedic diseases involving macrophages and their exosomes, including fracture healing, diabetic bone damage, osteosarcoma, and rheumatoid arthritis. In addition, we discuss the prospects and major challenges faced by macrophages and their exosomes in clinical practice.

The introduction of multidrug combination chemotherapy has significantly advanced the long-term survival prospects for osteosarcoma (OS) patients over the past decades. However, the escalating prevalence of chemoresistance has emerged as a substantial impediment to further advancements, necessitating the formulation of innovative strategies. Our present study leveraged sophisticated bulk and single-cell sequencing techniques to scrutinize the OS immune microenvironment, unveiling a potential association between the differentiation state of macrophages and the efficacy of OS chemotherapy. Notably, we observed that a heightened presence of lipid metabolism genes and pathways in predifferentiated macrophages, constituting the major cluster of OS patients exhibiting a less favorable response to chemotherapy. Subsequently, we developed a robust Macrophage and Lipid Metabolism (MLMR) risk model and a nomogram, both of which demonstrated commendable prognostic predictive performance. Furthermore, a comprehensive investigation into the underlying mechanisms of the risk model revealed intricate associations with variations in the immune response among OS patients. Finally, our meticulous drug sensitivity analysis identified a spectrum of potential therapeutic agents for OS, including AZD2014, Sapitinib, Buparlisib, Afuresertib, MIRA-1, and BIBR-1532. These findings significantly augment the therapeutic arsenal available to clinicians managing OS, presenting a promising avenue for elevating treatment outcomes.

All-trans retinoic acid (ATRA) is the most relevant and functionally active metabolite of Vitamin-A. From a therapeutic standpoint, ATRA is the first example of pharmacological agent exerting its anti-tumor activity via a cell differentiating action. In the clinics, ATRA is used in the treatment of Acute Promyelocytic Leukemia, a rare form of myeloid leukemia with unprecedented therapeutic results. The extraordinary effectiveness of ATRA in the treatment of Acute Promyelocytic Leukemia patients has raised interest in evaluating the potential of this natural retinoid in the treatment of other types of neoplasias, with particular reference to solid tumors.The present article provides an overview of the available pre-clinical and clinical studies focussing on ATRA as a therapeutic agent in the context of breast cancer from a holistic point of view. In detail, we focus on the direct effects of ATRA in breast cancer cells as well as the underlying molecular mechanisms of action. In addition, we summarize the available information on the action exerted by ATRA on the breast cancer micro-environment, an emerging determinant of the progression and invasive behaviour of solid tumors. In particular we discuss the recent evidences of ATRA activity on the immune system. Finally, we analyse and discuss the results obtained with the few ATRA-based clinical trials conducted in the context of breast cancer.

Tumor-associated macrophage (TAM) reprogramming is a promising therapeutic approach for cancer immunotherapy; however, its efficacy remains modest due to the low bioactivity of the recombinant cytokines used for TAM reprogramming. mRNA therapeutics are capable of generating fully functional proteins for various therapeutic purposes but accused for its poor sustainability. Inspired by kinetic energy recovery systems (KERS) in hybrid vehicles, a cytokine efficacy recovery system (CERS) is designed to substantially augment the therapeutic index of mRNA-based tumor immunotherapy via a "capture and stabilize" mechanism exerted by a nanostructured mineral coating carrying therapeutic cytokine mRNA. CERS remarkably recycles nearly 40% expressed cytokines by capturing them onto the mineral coating to extend its therapeutic timeframe, further polarizing the macrophages to strengthen their tumoricidal activity and activate adaptive immunity against tumors. Notably, interferon-γ (IFN-γ) produced by CERS exhibits ≈42-fold higher biological activity than recombinant IFN-γ, remarkably decreasing the required IFN-γ dosage for TAM reprogramming. In tumor-bearing mice, IFN-γ cmRNA@CERS effectively polarizes TAMs to inhibit osteosarcoma progression. When combined with the PD-L1 monoclonal antibody, IFN-γ cmRNA@CERS significantly boosts antitumor immune responses, and substantially prevents malignant lung metastases. Thus, CERS-mediated mRNA delivery represents a promising strategy to boost antitumor immunity for tumor treatment.

Upon heterodimerizing with other nuclear receptors, retinoid X receptors (RXR) act as ligand-dependent transcription factors, regulating transcription of critical signaling pathways that impact numerous hallmarks of cancer. By controlling both inflammation and immune responses, ligands that activate RXR can modulate the tumor microenvironment. Several small molecule agonists of these essential receptors have been synthesized. Historically, RXR agonists were tested for inhibition of growth in cancer cells, but more recent drug discovery programs screen new molecules for inhibition of inflammation or activation of immune cells. Bexarotene is the first successful example of an effective therapeutic that molecularly targets RXR; this drug was approved to treat cutaneous T cell lymphoma and is still used as a standard of care treatment for this disease. No additional RXR agonists have yet achieved FDA approval, but several promising novel compounds are being developed. In this review, we provide an overview of the multiple mechanisms by which RXR signaling regulates inflammation and tumor immunity. We also discuss the potential of RXR-dependent immune cell modulation for the treatment or prevention of cancer and concomitant challenges and opportunities.

Osteosarcoma is an extremely malignant tumor, and its pathogenesis is complex and remains incompletely understood. Most cases of osteosarcoma are accompanied by symptoms of bone loss or result in pathological fractures due to weakened bones. Enhancing the survival rate of osteosarcoma patients has proven to be a long-standing challenge. Numerous studies mentioned in this paper, including in-vitro, in-vivo, and in-situ studies have consistently indicated a close association between the symptoms of bone loss associated with osteosarcoma and the presence of osteoclasts. As the sole cells capable of bone resorption, osteoclasts participate in a malignant cycle within the osteosarcoma microenvironment. These cells interact with osteoblasts and osteosarcoma cells, secreting various factors that further influence these cells, disrupting bone homeostasis, and shifting the balance toward bone resorption, thereby promoting the onset and progression of osteosarcoma. Moreover, the interaction between osteoclasts and various other cells types, such as tumor-associated macrophages, myeloid-derived suppressor cells, DCs cells, T cells, and tumor-associated fibroblasts in the osteosarcoma microenvironment plays a crucial role in disease progression. Consequently, understanding the role of osteoclasts in osteosarcoma has sparked significant interest. This review primarily examines the physiological characteristics and functional mechanisms of osteoclasts in osteosarcoma, and briefly discusses potential therapies targeting osteoclasts for osteosarcoma treatment. These studies provide fresh ideas and directions for future research on the treatment of osteosarcoma.

M2 type tumor-associated macrophages, an essential component of the tumor microenvironment (TME), have been proved to contribute to tumor metastasis. Dauricine (Dau) has recently received widespread attention due to its multiple targets and low price. However, the effect of Dau on macrophage polarization of TME remains unclear. In this study, we investigated the effect of Dau on prostate cancer (PCa) metastasis and specifically its correlation to macrophage polarization. Our results showed that Dau efficiently suppressed M2 polarization of macrophages induced by interleukin (IL) -4 and IL-13. Mechanistically, Dau inhibited the activity of PI3K/AKT signaling pathway, which subsequently suppressed macrophage differentiation to M2 type. Importantly, our study indicated that Dau decreased the release of chitinase 3-like protein 1 (CHI3L1) from M2 macrophages, which ultimately inhibited the M2 macrophage-mediated progression of PCa cells in vitro and in vivo. Taken together, our data demonstrated that Dau suppressed M2 polarization of macrophages via downregulation of the PI3K/AKT signaling pathway, in turn, preventing proliferation, epithelial-mesenchymal transition, migration, and invasion of PCa cells. Thus, this study reveals a previously unrecognized function of Dau in inhibition of PCa progression via intervention in M2 polarization of macrophages.

The immune microenvironment of osteosarcoma (OS) has been reported to play an important role in disease progression and prognosis. However, owing to tumor heterogeneity, it is not ideal to predict OS prognosis by examining only infiltrating immune cells. This work aimed to build a prognostic gene signature based on similarities in the immune microenvironments of OS patients. Public datasets were used to examine the correlated genes, and the most consistent dominant infiltrating immune cell type was identified. The LASSO Cox regression model was used to establish a multiple-gene risk prediction signature. A nine-gene prognostic signature was generated from the correlated genes for M0 macrophages and then proven to be effective and reliable in validation cohorts. Signature comparison indicated the priority of the signature. Multivariate Cox regression models indicated that the signature risk score is an independent prognostic factor for OS patients regardless of the Huvos grade in all datasets. In addition, the results of the association between the signature risk score and chemotherapy sensitivity also showed that there was no significant difference in the sensitivity of any drugs between the low- and high-risk groups. A GSEA of GO and KEGG pathways found that antigen processing- and presentation-related biological functions and olfactory transduction receptor signaling pathways have important roles in signature functioning. Our findings showed that M0 macrophages were the dominant infiltrating immune cell type in OS and that the new gene signature is a promising prognostic model for OS patients.

Osteosarcoma (OS) is a heterogeneous, highly metastatic bone malignancy in children and adolescents. Despite advancements in multimodal treatment strategies, the prognosis for patients with metastatic or recurrent disease has not improved significantly in the last four decades. OS is a highly heterogeneous tumor; its genetic background and the mechanism of oncogenesis are not well defined. Unfortunately, no effective molecular targeted therapy is currently available for this disease. Understanding osteosarcoma's tumor microenvironment (TME) has recently gained much interest among scientists hoping to provide valuable insights into tumor heterogeneity, progression, metastasis, and the identification of novel therapeutic avenues. Here, we review the current understanding of the TME of OS, including different cellular and noncellular components, their crosstalk with OS tumor cells, and their involvement in tumor progression and metastasis. We also highlight past/current clinical trials targeting the TME of OS for effective therapies and potential future therapeutic strategies with negligible adverse effects.

Chemoimmunotherapy is an area of active research and development with a growing body of evidence supporting its potential benefits for the treatment of cancer. However, chemotherapy components of chemoimmunotherapy have several limitations, including systemic toxicity and poor performance in reversing the immunosuppressive tumor microenvironment. Here, we designed a twin drug, MROP, complexed with all-trans retinoic acid and oxaliplatin, and showed that the twin drug significantly enhanced the synergetic therapeutic efficacy with anti-PD-1 in a colorectal cancer mouse model. We demonstrated by mechanistic analyses of tumor tissue that the combination of anti-PD-1 and MROP induced immunogenic cell death and regulated tumor-infiltrating immune cells, including the polarization of tumor-associated macrophages toward type 1, a reduction in myeloid-derived suppressor cells, and a significant increase in the proportion of T cells, particularly CD8+ T cells. This paper provides a promising strategy for cancer treatment and new insight into the mechanism of chemoimmunotherapy.

Bone tumors, including primary bone tumors and bone metastases, have been plagued by poor prognosis for decades. Although most tumor tissue is removed, clinicians are still confronted with the dilemma of eliminating residual cancer cells and regenerating defective bone tissue after surgery. Therefore, functional biomaterial scaffolds are considered to be the ideal candidates to bridge defective tissues and restrain cancer recurrence. Through functionalized structural modifications or coupled therapeutic agents, they provide sufficient mechanical strength and osteoinductive effects while eliminating cancer cells. Numerous novel approaches such as photodynamic, photothermal, drug-conjugated, and immune adjuvant-assisted therapies have exhibited remarkable efficacy against tumors while exhibiting low immunogenicity. This review summarizes the progress of research on biomaterial scaffolds based on different functionalization strategies in bone tumors. We also discuss the feasibility and advantages of the combined application of multiple functionalization strategies. Finally, potential obstacles to the clinical translation of anti-tumor bone bioscaffolds are highlighted. This review will provide valuable references for future advanced biomaterial scaffold design and clinical bone tumor therapy.

The cure rate for metastatic or relapsed osteosarcoma has not substantially improved over the past decades despite the exploitation of multimodal treatment approaches, allowing long-term survival in less than 30% of cases. Patients with osteosarcoma often develop resistance to chemotherapeutic agents, where personalized targeted therapies should offer new hope. T cell immunotherapy as a complementary or alternative treatment modality is advancing rapidly in general, but its potential against osteosarcoma remains largely unexplored. Strategies incorporating immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) modified T cells, and T cell engaging bispecific antibodies (BsAbs) are being explored to tackle relapsed or refractory osteosarcoma. However, osteosarcoma is an inherently heterogeneous tumor, both at the intra- and inter-tumor level, with no identical driver mutations. It has a pro-tumoral microenvironment, where bone cells, stromal cells, neovasculature, suppressive immune cells, and a mineralized extracellular matrix (ECM) combine to derail T cell infiltration and its anti-tumor function. To realize the potential of T cell immunotherapy in osteosarcoma, an integrated approach targeting this complex ecosystem needs smart planning and execution. Herein, we review the current status of T cell immunotherapies for osteosarcoma, summarize the challenges encountered, and explore combination strategies to overcome these hurdles, with the ultimate goal of curing osteosarcoma with less acute and long-term side effects.

Immunotherapies are a promising therapeutic option, yet for a variety of reasons, these treatments have achieved limited success against sarcomas. The immunosuppressive tumor microenvironment (TME) of sarcomas as well as lack of predictive biomarkers, decreased T-cell clonal frequency, and high expression of immunosuppressive infiltrating cells has thus far prevented major success using immunotherapies. By breaking down the TME into its individual components and understanding how the various cell types interact with each other as well as in the context of the complex immune microenvironment, can lead to effective therapeutic immunotherapy treatments, potentially improving outcomes for those with metastatic disease.

This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease.

Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme. The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. It is characterized by a rapid progression, poor prognosis, and early pulmonary metastasis. Over the past 30 years, approximately 85% of patients with osteosarcoma have experienced metastasis. The five-year survival of patients with lung metastasis during the early stages of treatment is less than 20%. The tumor microenvironment (TME) not only provides conditions for tumor cell growth but also releases a variety of substances that can promote the metastasis of tumor cells to other tissues and organs. Currently, there is limited research on the role of the TME in osteosarcoma metastasis. Therefore, to explore methods for regulating osteosarcoma metastasis, further investigations must be conducted from the perspective of the TME. This will help to identify new potential biomarkers for predicting osteosarcoma metastasis and assist in the discovery of new drugs that target regulatory mechanisms for clinical diagnosis and treatment. This paper reviews the research progress on the mechanism of osteosarcoma metastasis based on TME theory, which will provide guidance for the clinical treatment of osteosarcoma.

Myocardial ischemia-reperfusion injury (MIRI) remains an unsolved puzzle in medical circles. Naringenin (NAR) is a flavonoid with cardioprotective potential. The purpose of this article was to discuss the protective mechanism of NAR in MIRI by regulating macrophage polarization. The MIRI mouse model was established and perfused with NAR before surgery. In the in vitro experiment, macrophages RAW264.7 were treated with lipopolysaccharide to induce M1 polarization after pretreatment with NAR. Rescue experiments were carried out to validate the functions of transcription factor EB (TFEB), the NLR pyrin domain containing 3 (NLRP3) inflammasome, and autophagy in macrophage polarization. NAR reduced histopathological injury and infarction of myocardial tissues in MIRI mice, inhibited M1 polarization and promoted M2 polarization of macrophages, diminished levels of pro-inflammatory factors, and augmented levels of anti-inflammatory factors. NAR facilitated TFEB nuclear translocation and inhibited the NLRP3 inflammasome pathway. Silencing TFEB or Nigericin partly nullified the effect of NAR on macrophage polarization. NAR increased autophagosome formation, autophagy flux, and autophagy level. Autophagy inhibitor 3-methyladenine partly invalidated the inhibition of NAR on the NLRP3 inflammasome pathway. In animal experiments, NAR protected MIRI mice through the TFEB-autophagy-NLRP3 inflammasome pathway. Collectively, NAR inhibited NLRP3 inflammasome activation and facilitated M2 macrophage polarization by stimulating TFEB nuclear translocation, thus protecting against MIRI.

Immune cell infiltration into the tumor microenvironment is associated with cancer prognosis. Tumor-associated macrophages play essential roles in tumor initiation, progression, and metastasis. Follistatin-like protein 1 (FSTL1), a widely expressed glycoprotein in human and mouse tissues, is a tumor suppressor in various cancers and a regulator of macrophage polarization. However, the mechanism by which FSTL1 affects crosstalk between breast cancer cells and macrophages remains unclear. By analyzing public data, we found that FSTL1 expression was significantly low in breast cancer tissues compared to normal breast tissues, and high expression of FSTL1 in patients indicated prolonged survival. Using flow cytometry, we found that total and M2-like macrophages dramatically increased in the metastatic lung tissues during breast cancer lung metastasis in Fstl1+/- mice. Transwell assay in vitro and q-PCR experimental results showed that FSTL1 inhibited macrophage migration toward 4T1 cells by decreasing CSF1, VEGF-α, and TGF-β secretion in 4T1 cells. We demonstrated that FSTL1 inhibited M2-like tumor-associated macrophage recruitment toward the lungs by suppressing CSF1, VEGF-α, and TGF-β secretion in 4T1 cells. Therefore, we identified a potential therapeutic strategy for triple-negative breast cancer.

Tumour-associated macrophages (TAMs) often promote cancer progression through immunosuppression in the tumour microenvironment (TME). However, the signalling pathways crosstalk responsible for this mechanism remain unclear. The aim of our study was to investigate whether the interaction between TAMs and colorectal cancer cells could be down-regulated by nanoparticles (NPs) loaded with retinoic acid (RA) and coated with cholesterol (CHO), in combination with an anti-PD-L1 immune checkpoint inhibitor. Tumours were evaluated by qRT-PCR and immunohistochemistry from allographic tumour growth model. In addition, human tumours were evaluated by Tissue Microarray (TMA) and immunohistochemistry. Complementary analysis of epithelial-mesenchymal transition, cell migration, and macrophage polarisation were evaluated in vitro. We showed that the IL-10R/IL-10 axis is involved in overstimulation of the STAT3 pathway as well as downregulation of the NF-κB signalling pathway, which supports a loop of immunosuppressive cytokines that induces the M2-TAM phenotype. Furthermore, our combined findings suggest that the upregulation of STAT3/NF-κB pathways crosstalk mediated by immunosuppressive cytokines, such as IL-10/PD-L1/TGF-β, via M2-TAMs in the TME, leads to immunosuppression and epithelial-mesenchymal-transition of the colorectal cancer for stimulating Vimentin, CXCL12 and CD163 in the primary tumours. Importantly, NPs holding RA and coated with CHO in combination with anti-PD-L1 were more efficient in blocking this signalling pathway. These results contribute to our understanding of the immunological mechanisms, especially the re-educating of TAMs, and provide a novel management strategy for aggressive colorectal cancers using anti-PD-L1-conjugated nanocarriers.

Osteosarcoma is one of the most common malignant tumors in children and tends to occur around the knee. Problems such as recurrence and metastasis are the outcomes of traditional treatment methods. One of the reasons for these issues is the infiltration of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Photothermal immunotherapy has emerged as one of the most potent approaches for cancer treatment. In this study, we designed a biodegradable, injectable, and photothermal hydrogel that functions to reprogram TAMs into classically activated macrophages (M1) based on hydroxypropyl chitin (HPCH), tannic acid and ferric ions (HTA). We found that HTA had better photothermal efficiency than a pure hydrogel; its photothermal repeatability is good and it can be NIR (808 nm) irradiated as needed. In addition, the precooled hydrogel solution can be injected into the tumor and it can rapidly gel in situ. In vitro, HTA with NIR irradiation (HTA + NIR) induced the apoptosis of K7M2 cancer cells. In vivo, the local administration of HTA + NIR exerted photothermal killing of primary tumors and reprogramming of TAMs into M1-type macrophages in the TME. Therefore, the injectable photothermally active antitumor hydrogel has great potential for modulating the TME to treat bone tumors.

Macrophages are versatile immune cells and can adapt to both external stimuli and their surrounding environment. Macrophages are categorized into two major categories; M1 macrophages release pro-inflammatory cytokines and produce protective responses that lead to antimicrobial or antitumor activity. M2 or tumor-associated macrophages (TAM) release anti-inflammatory cytokines that support tumor growth, invasion capacity, and metastatic potential. Since macrophages can be re-polarized from an M2 to an M1 phenotype with a variety of strategies, this has emerged as an innovative anti-cancer approach. Osteosarcoma (OS) is a kind of bone cancer and consists of a complex niche, and immunotherapy is not very effective. Therefore, immediate attention to new strategies is required. We incorporated the recent studies that have used M2-M1 repolarization strategies in the aspect of treating OS cancer.

Numerous studies have demonstrated the key roles of tumor-associated macrophages (TAMs) in osteosarcoma metastasis. Higher levels of high mobility group box 1 (HMGB1) promote osteosarcoma progression. However, whether HMGB1 is involved in the polarization of M2 macrophages into M1 macrophages in osteosarcoma remains largely unknown. Here, HMGB1 and CD206 mRNA expression levels were measured by a quantitative reverse transcription-polymerase chain reaction in osteosarcoma tissues and cells. HMGB1 and receptor for advanced glycation end products (RAGE) protein expression levels were measured by western blotting. Osteosarcoma migration was measured using transwell and wound-healing assays, while a transwell assay determined osteosarcoma invasion. Macrophage subtypes were detected using flow cytometry. HMGB1 expression levels were aberrantly enhanced in osteosarcoma tissues compared with normal tissues and were positively correlated with AJCC III and IV stages, lymph node metastasis, and distant metastasis. Silencing HMGB1 inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. Furthermore, reduced HMGB1 expression levels in conditioned media derived from osteosarcoma cells induced the polarization of M2 TAMs to M1 TAMs. In addition, silencing HMGB1 inhibited the liver and lung metastasis of tumors and reduced the expression levels of HMGB1, CD163, and CD206 in vivo. HMGB1 was found to regulate macrophage polarization through RAGE. Polarized M2 macrophages induced osteosarcoma migration and invasion, activating HMGB1 expression in osteosarcoma cells to form a positive feedback loop. In conclusion, HMGB1 and M2 macrophages enhanced osteosarcoma migration, invasion, and EMT through positive feedback regulation. These findings reveal the significance of tumor cell and TAM interactions in the metastatic microenvironment.

Osteosarcoma is the most frequent primary bone tumor with a poor prognosis. Immune infiltration proved to have a strong impact on prognosis. We analyzed single-cell datasets and bulk datasets to confirm the main immune cell populations and their properties in osteosarcoma.

The examples in bulk datasets GSE21257 and GSE32981 from the Gene Expression Omnibus database were divided into two immune infiltration level groups, and 34 differentially expressed genes were spotted. Then, we located these genes among nine major cell clusters and their subclusters identified from 99,668 individual cells in single-cell dataset GSE152048 including 11 osteosarcoma patients. Especially, the markers of all kinds of myeloid cells identified in single-cell dataset GSE152048 were set to gene ontology enrichment. We clustered the osteosarcoma samples in the TARGET-OS from the Therapeutically Applicable Research to Generate Effective Treatments dataset into two groups by complete component 1q positive macrophage markers and compared their survival.

Compared with the low-immune infiltrated group, the high-immune infiltrated group showed a better prognosis. Almost all the 34 differentially expressed genes expressed higher or exclusively among myeloid cells. A group of complete component 1q-positive macrophages was identified from the myeloid cells. In the bulk dataset TARGET-OS, these markers and the infiltration of complete component 1q-positive macrophages related to longer survival.

Complete component 1q-positive tumor-associated macrophages were the major immune cell population in osteosarcoma, which contributed to a better prognosis.

In osteosarcoma patients, metastasis of the primary cancer is the leading cause of death. At present, management options to prevent metastasis are limited and non-curative. In this study, we review the current state of knowledge on the molecular mechanisms of metastasis and discuss promising new therapies to combat osteosarcoma metastasis. Genomic and epigenomic changes, metabolic reprogramming, transcription factors, dysregulation of physiologic pathways, and alterations to the tumor microenvironment are some of the changes reportedly involved in the regulation of osteosarcoma metastasis. Key factors within the tumor microenvironment include infiltrating lymphocytes, macrophages, cancer-associated fibroblasts, platelets, and extracellular components such as vesicles, proteins, and other secreted molecules. We conclude by discussing potential osteosarcoma-limiting agents and their clinical studies.

Osteosarcoma (OS) is a common primary malignant tumor of the bone in children and adolescents. The five-year survival rate is estimated to be ~70% based on the currently available treatment modalities. It is well known that tumor-infiltrating immune cells (TIICs) that are the most important components in the tumor microenvironment can exert a killing effect on tumor cells. Therefore, in the present study, 85 RNA-sequencing OS samples were categorized into high- and low-immune score groups with ESTIAMATE. Based on the immune score groups, 474 differentially expressed genes (DEGs) were acquired using the LIMMA package of R language. Subsequently, 86 DEGs were taken through univariate COX regression analysis, of which 14 were screened out by least absolute shrinkage and selection operator regression analysis. Furthermore, multivariate COX regression analysis was performed to obtain 4 DEGs. Finally, ecotropic virus integration site 2B (EVI2B) or CD361 gene was screened out via Kaplan-Meier analysis. In addition, CIBERSORT algorithm was used to evaluate the proportion of 22 kinds of TIICs in OS. Correlation analysis revealed that the high expression level of EVI2B can elevate the infiltrated proportion of CD8⁺ T cells. Moreover, analysis of single cell RNA-sequencing transcriptome datasets and immunohistochemical staining uncovered that EVI2B was mainly expressed on CD8⁺ T cells and that EVI2B could promote the expression of granzyme A and K of CD8⁺ T cells to exhibit a potent killing effect on tumor cells. Therefore, EVI2B was identified as a protective immune-related gene and contributed to good prognosis in OS patients.

Osteosarcoma is a primary bone tumor with a high mortality rate. The event-free survival rate has not improved significantly in the past 30 years, which brings a heavy burden to patients and society. The high heterogeneity of osteosarcoma leads to the lack of specific targets and poor therapeutic effect. Tumor microenvironment is the focus of current research, and osteosarcoma is closely related to bone microenvironment. Many soluble factors and extracellular matrix secreted by many cells in the bone microenvironment have been shown to affect the occurrence, proliferation, invasion and metastasis of osteosarcoma through a variety of signaling pathways. Therefore, targeting other cells in the bone microenvironment may improve the prognosis of osteosarcoma. The mechanism by which osteosarcoma interacts with other cells in the bone microenvironment has been extensively investigated, but currently developed drugs targeting the bone microenvironment have poor efficacy. Therefore, we review the regulatory effects of major cells and physical and chemical properties in the bone microenvironment on osteosarcoma, focusing on their complex interactions, potential therapeutic strategies and clinical applications, to deepen our understanding of osteosarcoma and the bone microenvironment and provide reference for future treatment. Targeting other cells in the bone microenvironment may provide potential targets for the development of clinical drugs for osteosarcoma and may improve the prognosis of osteosarcoma.

We argue here that in many ways, Ewing sarcoma (EwS) is a unique tumor entity and yet, it shares many commonalities with other immunologically cold solid malignancies. From the historical perspective, EwS, osteosarcoma (OS) and other bone and soft-tissue sarcomas were the first types of tumors treated with the immunotherapy approach: more than 100 years ago American surgeon William B. Coley injected his patients with a mixture of heat-inactivated bacteria, achieving survival rates apparently higher than with surgery alone. In contrast to OS which exhibits recurrent somatic copy-number alterations, EwS possesses one of the lowest mutation rates among cancers, being driven by a single oncogenic fusion protein, most frequently EWS-FLI1. In spite these differences, both EwS and OS are allied with immune tolerance and low immunogenicity. We discuss here the potential mechanisms of immune escape in these tumors, including low representation of tumor-specific antigens, low expression levels of MHC-I antigen-presenting molecules, accumulation of immunosuppressive M2 macrophages and myeloid proinflammatory cells, and release of extracellular vesicles (EVs) which are capable of reprogramming host cells in the tumor microenvironment and systemic circulation. We also discuss the vulnerabilities of EwS and OS and potential novel strategies for their targeting.

Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy (ACT) against solid tumors. Here, we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors. Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8⁺ T cells, which led to improved antitumor outcomes. Mechanistically, infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation. Overall, we presented a simple, cost-effective, and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.