Breast cancer ranks as the most prevalent cancer type impacting women globally, both in terms of incidence and mortality rates, making it a major health concern for females. There's an urgent requirement to delve into new cancer treatment methods to improve patient survival rates.

Immunotherapy has gained recognition as a promising area of research in the treatment of breast cancer, with targeted immune checkpoint therapies demonstrating the potential to yield sustained clinical responses and improve overall survival rates. Presently, the predominant immune checkpoints identified on breast cancer cells include CD47, CD24, PD-L1, MHC-I, and STC-1, among others. Nevertheless, the specific roles of these various immune checkpoints in breast carcinogenesis, metastasis, and immune evasion have yet to be comprehensively elucidated. We conducted a comprehensive review of the existing literature pertaining to breast cancer and immune checkpoint inhibitors, providing a summary of findings and an outlook on future research directions.

This article reviews the advancements in research concerning each immune checkpoint in breast cancer and their contributions to immune evasion, while also synthesizing immunotherapy strategies informed by these mechanisms. Furthermore, it anticipates future research priorities, thereby providing a theoretical foundation to guide immunotherapy as a potential interventional approach for breast cancer treatment.

Knowledge of immune checkpoints will drive the creation of novel cancer therapies, and future breast cancer research will increasingly emphasize personalized treatments tailored to patients' specific tumor characteristics.

The CD47/SIRPα axis conveys a 'don't eat me' signal, thereby thwarting the phagocytic clearance of tumor cells. Although blocking antibodies targeting CD47 have demonstrated promising anti-tumor effects in preclinical models, clinical trials involving human cancer patients have not yielded ideal results. Exploring the regulatory mechanisms of CD47 is imperative for devising more efficacious combinational therapies. Here, we report that inhibiting USP2 prompts CD47 degradation and reshapes the tumor microenvironment (TME), thereby enhancing anti-PD-1 immunotherapy. Mechanistically, USP2 interacts with CD47, stabilizing it through deubiquitination. USP2 inhibition destabilizes CD47, thereby boosting macrophage phagocytosis. Single-cell RNA sequencing shows USP2 inhibition reprograms TME, evidenced by increasing M1 macrophages and CD8+ T cells while reducing M2 macrophages. Combining ML364 with anti-PD-1 reduces tumor burden in mouse models. Clinically, low USP2 expression predicts a better response to anti-PD-1 treatment. Our findings uncover the regulatory mechanism of CD47 by USP2 and targeting this axis boosts anti-tumor immunity.

Neutrophils are among the most abundant immune cell types in the tumour microenvironment and have been associated with poor outcomes across multiple cancer types. Yet despite mounting evidence of their role in tumour progression, therapeutic strategies targeting neutrophils have only recently gained attention and remain limited in scope. This is probably due to the increasing number of distinct neutrophil subtypes identified in cancer and the limited understanding of the mechanisms by which these subsets influence tumour progression and immune evasion. In this Review, we discuss the spectrum of neutrophil subtypes - including those with antitumour activity - and their potential to polarize towards tumour-suppressive phenotypes. We explore the molecular pathways and effector functions by which neutrophils modulate cancer progression, with an emphasis on identifying tractable therapeutic targets. Finally, we examine emerging clinical trials aimed at modulating neutrophil lineages and consider their implications for patient outcomes.

Myelodysplastic neoplasms (MDS) represent a heterogeneous group of malignant hematopoietic stem and progenitor cell (HSPC) disorders characterized by cytopenia, ineffective hematopoiesis, as well as the potential to progress to acute myeloid leukemia (AML). The pathogenesis of MDS is influenced by intrinsic factors, such as genetic insults, and extrinsic factors, including altered bone marrow microenvironment (BMM) composition and architecture. BMM is reprogrammed in MDS, initially to prevent the development of the disease but eventually to provide a survival advantage to dysplastic cells. Recently, inflammation or age-related inflammation in the bone marrow has been identified as a key pathogenic mechanism for MDS. Inflammatory signals trigger stress hematopoiesis, causing HSPCs to emerge from quiescence and resulting in MDS development. A better understanding of the role of the BMM in the pathogenesis of MDS has opened up new avenues for improving diagnosis, prognosis, and treatment of the disease. This article provides a comprehensive review of the current knowledge regarding the significance of the BMM to MDS pathophysiology and highlights recent advances in developing innovative therapies.

Tumor-associated macrophages (TAMs) contribute to tumor progression by promoting angiogenesis, remodeling the tumor extracellular matrix, inducing tumor invasion and metastasis, as well as immune evasion. Due to the high plasticity of TAMs, they can polarize into different phenotypes with distinct functions, which are primarily categorized as the pro-inflammatory, anti-tumor M1 type, and the anti-inflammatory, pro-tumor M2 type. Notably, anti-tumor macrophages not only directly phagocytize tumor cells, but also present tumor-specific antigens and activate adaptive immunity. Therefore, targeted regulation of TAMs to unleash their potential anti-tumor capabilities is crucial for improving the efficacy of cancer immunotherapy. Nanomedicine serves as a promising vehicle and can inherently interact with TAMs, hence, emerging as a new paradigm in cancer immunotherapy. Due to their controllable structures and properties, nanomedicines offer a plethora of advantages over conventional drugs, thus enhancing the balance between efficacy and toxicity. In this review, we provide an overview of the hallmarks of TAMs and discuss nanomedicines for targeting TAMs with a focus on inhibiting recruitment, depleting and reprogramming TAMs, enhancing phagocytosis, engineering macrophages, as well as targeting TAMs for tumor imaging. We also discuss the challenges and clinical potentials of nanomedicines for targeting TAMs, aiming to advance the exploitation of nanomedicine for cancer immunotherapy.

Cancer-associated fibroblasts (CAFs) display significant functional and molecular heterogeneity within the tumor microenvironment, playing diverse roles in cancer progression. Employing single-cell RNA sequencing data of colorectal cancer (CRC), we identified a subset of matrix CAFs (mCAFs) as a critical subtype that secretes THBS2, a molecule linked to advanced cancer stages and poor prognosis. Spatial transcriptomics and multiplex immunohistochemistry revealed clear spatial colocalization between THBS2-producing mCAFs and tumor cells. Mechanically, CAF-secreted THBS2 binds to CD47 on tumor cells, triggering the MAPK/ERK5 signaling pathway, which enhances tumor progression. The tumor-promoting role of THBS2 was further validated using fibroblast-specific THBS2 knockout mice, patient-derived organoids, and xenografts. Moreover, the transcription factor CREB3L1 was identified as a regulator of the transformation of normal fibroblasts into THBS2-producing mCAFs. These findings underscore the pivotal role of THBS2 in CRC progression and highlight the therapeutic potential of targeting the THBS2-CD47 axis and CREB3L1 in CRC.

Cadherin 17 (CDH17) is highly expressed in digestive system cancers, and the potential of nanobodies targeting CDH17 as imaging probes and delivery vehicles for radioactive β-particles warrants exploration for their theranostic potential in CDH17-overexpressing gastric cancer (GC). In this study, we screened an anti-CDH17 nanobody library and constructed two antibodies: anti-CDH17 VHH (recombinant nanobody fused with a polyhistidine tag) and anti-CDH17 VHH-ABD (recombinant nanobody fused with an albumin-binding domain). VHH targeting CDH17 and its derivative VHH-ABD were conjugated with DOTA and labeled with radionuclide 177Lu. The pharmacokinetics and theranostic efficacy of these agents were evaluated in the GC xenograft models. [177Lu]Lu-VHH and [177Lu]Lu-VHH-ABD exhibited high radiochemical purity (>99%, n = 3) and successfully delineated CDH17-positive gastric cancer tissues on SPECT/CT imaging. Compared with the rapid renal clearance of [177Lu]Lu-VHH, [177Lu]Lu-VHH-ABD demonstrated prolonged circulation times with increased and sustained tumor accumulation. Survival experiments in the MKN-45 tumor model revealed that two doses of [177Lu]Lu-VHH-ABD effectively suppressed tumor growth, with limited systemic biotoxicity. Histological analysis using hematoxylin and eosin (H&E) staining and Ki67 immunohistochemistry confirmed structural disruption and low tumor cell proliferative activity in the tumor tissue. In preclinical studies, [177Lu]Lu-anti-CDH17 VHH-ABD demonstrated substantial antitumor efficacy with manageable toxicity, offering promising clinical potential as a viable therapeutic option for CDH17-overexpressing GC.

CD47 is a cell-surface glycoprotein that is expressed on normal human tissues and plays a key role as a marker of self. Tumor cells have co-opted CD47 overexpression to evade immune surveillance, and thus blockade of CD47 is a highly active area of clinical exploration in oncology. However, clinical development of CD47-targeted agents has been complicated by its robust expression in normal tissues and the toxicities that arise from blocking this inhibitory signal. Furthermore, pro-phagocytic signals are not uniformly expressed in tumors, and antibody blockade alone is often not sufficient to drive antitumor activity. The inclusion of an IgG1 antibody backbone into therapeutic design has been shown to not only serve as an additional pro-phagocytic signal but also exacerbate toxicities in normal tissues. Therefore, a need persists for more selective therapeutic modalities targeting CD47. To address these challenges, we developed SGN-CD47M, a humanized anti-CD47 IgG1 mAb linked to novel masking peptides through linkers designed to be cleaved by active proteases enriched in the tumor microenvironment (TME). Masking technology has the potential to increase the amount of drug that reaches the TME while concomitantly reducing systemic toxicities. We demonstrate that SGN-CD47M is well tolerated in cynomolgus monkeys and displays a 20-fold improvement in tolerability to hematologic toxicities when compared with the unmasked antibody. SGN-CD47M also displays preferential activation in the TME that leads to robust single-agent antitumor activity. For these reasons, SGN-CD47M may have enhanced antitumor activity and improved tolerability relative to existing therapies that target the CD47-signal regulatory protein α interaction.

CD47 inhibits host cell phagocytosis by macrophages, leading to immune evasion. Upregulation of CD47 in many cancers including hematopoietic neoplasms correlates with poor prognosis. We evaluated CD47 expression in classic follicular lymphoma (FL) to ascertain its potential utility for targeted therapy. A cohort of 97 cases were studied by immunohistochemistry using a rabbit anti-CD47 monoclonal antibody and the results were correlated with clinicopathologic features, gene expression and clinical outcome. Our findings show that high CD47 expression (H-score ≥150) was significantly associated with a worse event-free survival at 12 months EFS12 and EFS24 months (P = 0.023 and 0.009 respectively), although no correlation was seen with overall survival (OS; P = 0.175) or other clinicopathologic parameters. In multivariate analysis, H-score retained its impact on both EFS12 and EFS24 (P = 0.027 and 0.0.012, respectively). Gene expression profiling revealed 11 genes that showed statistically significant differences in CD47-high versus CD47-low expressors in univariate but not in multivariate analysis and included MAPK12 and CCND2. Validation in larger case cohorts is required to further support the potential application of CD47-targeted approaches in patients with FL and to explore novel therapeutic strategies. In addition, differentially expressed genes in CD47-high versus CD47-low expressors raises potential areas of interest for further study.

Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is a severe, frequently lethal condition. Oncogene addiction to epidermal growth factor receptor (EGFR) is a hallmark of HNSCC, but the clinical efficacy of EGFR-targeted therapies remains low. Understanding molecular networks governing EGFR-driven progression is paramount to the exploration of (co)-treatment targets and predictive markers.

We performed function-based mapping of differentially expressed genes in EGFR-mediated local invasion (fDEGs) using photoconvertible tracers and RNA-sequencing (RNA-seq) in a cellular 3D-model.

Upon alignment with public single-cell RNA-seq (scRNA-seq) datasets and HNSCC-specific regulons, a gene regulatory network of local invasion (invGRN) was inferred from gene expression data, which was overrepresented in budding tumors. InvGRN comprises the central hubs inhibin subunit beta alpha (INHBA) and snail family transcriptional repressor 2 (SNAI2), and druggable fDEGs integrin subunit beta 4 (ITGB4), laminin 5 (LAMB3/LAMC2), and sphingosine kinase 1 (SPHK1). Blockade of INHBA repressed local invasion and was reverted by activin A, laminin 5, and sphingosine-1-phosphate, demonstrating a functional interconnectivity of the invGRN. Epithelial-to-mesenchymal transition (EMT) of malignant cells and the invGRN are induced by newly defined EGFR-activity subtypes with prognostic value that are promoted by amphiregulin (AREG) and epiregulin (EREG). Importantly, co-inhibition of SPHK1 showed synthetic effects on Cetuximab-mediated invasion blockade and high expression of selected fDEGs was associated with response to Cetuximab in patient-derived xenotransplantation (PDX) and R/M-HNSCC patients.

We describe an actionable network of EGFR-mediated local invasion and define druggable effectors with predictive potential regarding the response of R/M-HNSCC to Cetuximab.

Triple-negative breast cancer (TNBC), defined by the absence of ER, PR, and Her2, impacts over 46,000 U.S. women annually, disproportionately affecting minority ethnic groups and individuals with BRCA1 mutations. Despite advancements such as PARP inhibitors, TNBC remains highly aggressive, with frequent recurrences and a 50% mortality rate within four years, underscoring the urgent need for more effective targeted therapies. MicroRNAs (miRNAs) represent a novel therapeutic approach. In TNBC, overexpressed miR-21 drives tumor progression, immune evasion, treatment resistance, and metastasis. Targeted miR-21 inhibition could curb these effects while minimizing harm to normal cells. We developed a peptide-conjugated miR-21 inhibitor targeting TNBC cells via the overexpressed IGF1 receptor (IGF1R), associated with poor prognosis. Using aminomethyl-bridged nucleic acid (BNA) chemistry, a serum-stable, low-toxicity anti-miR-21 RNA analog was created and tested for its effects on TNBC cell proliferation, apoptosis, tumor suppressor expression, and immune checkpoint regulation. Conjugation to an IGF1 peptide analog improved delivery, demonstrating tumor-specific biodistribution, efficacy, and safety in TNBC-bearing mice. The miR-21 inhibitor-peptide conjugate reduced proliferation, induced apoptosis, elevated tumor suppressors, and suppressed immune checkpoints in TNBC cell lines. In vivo , it targeted tumors, halted growth, and showed no liver or kidney toxicity, supporting its potential as a targeted, low-toxicity TNBC therapy.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in a variety of cell types and are involved in multiple physiological regulatory mechanisms in cells, tissues and systems. Increasing evidence suggests that the α5 nicotinic acetylcholine receptor (α5-nAChR), encoded by the CHRNA5 gene, is one of a key mediator involved in lung cancer development and immune responses. Several studies have shown that it is a regulator that stimulates processes via various signaling pathways, including STAT3 in lung cancer. In addition, α5-nAChR has a profound effect on lung immune response through multiple immune-related factor pathways. In this review, we focus on the perspectives on α5-nAChR in lung cancer progression, which indicates that targeting α5-nAChR could provide novel anticancer and immune therapy strategies for lung cancer.

Cancer-associated myeloid cells due to their plasticity play dual roles in both promoting and inhibiting tumor progression. Myeloid cells with immunosuppressive properties play a critical role in anti-cancer immune regulation. Cells of different origin, such as tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), myeloid derived suppressor cells (also called MDSCs) and eosinophils are often expanded in cancer patients and significantly influence their survival, but also the outcome of anti-cancer therapies. For this reason, the variety of preclinical and clinical studies to modulate the activity of these cells have been conducted, however without successful outcome to date. In this review, pro-tumor activity of myeloid cells, myeloid cell-specific therapeutic targets, in vivo studies on myeloid cell re-polarization and the impact of myeloid cells on immunotherapies/genetic engineering are addressed. This paper also summarizes ongoing clinical trials and the concept of chimeric antigen receptor macrophage (CAR-M) therapies, and suggests future research perspectives, offering new opportunities in the development of novel clinical treatment strategies.

Immune checkpoint (ICP) blockade has shown limited effectiveness in glioblastoma (GBM), particularly in the mesenchymal subtype, where interactions between immune cells and glioblastoma cancer stem cells (GSCs) drive immunosuppression and therapy resistance. Tailoring ICPs specific to GSCs can enhance the antitumor immune response. This study proposes the use of lipid nanoparticles (LNPs) encapsulating CRISPR RNAs as an in vivo screening tool for ICPs in a syngeneic model of mesenchymal GSCs. Using PD-L1 and CD47 to validate the proof of concept, intratumoral administration of LNPs in orthotopic tumors achieved efficient editing of ICPs, leading to enhanced immune cell infiltration within the tumor microenvironment. Targeting CD47 reduced tumor growth, suggesting improved cancer cell sensitization to the immune system post-ICP editing. The study positions LNPs as a robust tool for in vivo validation of ICPs as therapeutic targets in clinically relevant GBM models. LNPs could serve as a screening tool in patient-derived xenografts to identify and optimize ICP combinations, potentially expediting ICP translation and enhancing personalized GBM immunotherapies.

Mononuclear phagocytes (MPs), which consist of dendritic cells, monocytes, and macrophages, are distributed throughout the body and actively eliminate invading microorganisms and abnormal cells. Depending on the local microenvironment, MPs manifest considerably various lifespans and phenotypes to maintain tissue homeostasis. Vascular-associated mononuclear phagocytes (VaMPs) are the special subsets of MPs that are localized either within the lumen side or on the apical surface of vessels, acting as the critical sentinels to recognize and defend against disseminated tumor cells. In this review, we introduce three major types of VaMPs, patrolling monocytes, Kupffer cells, and perivascular macrophages, and discuss their emerging roles in immunosurveillance during incipient metastasis. We also explore the roles of lineage-determining transcription factors and cell surface receptors that endow VaMPs with potent anti-tumor activity. Finally, we highlight the molecular and cellular mechanisms that drive the phenotypic plasticity of VaMPs and summarize combinatory strategies for targeting VaMPs in overt metastasis.

Acute liver failure (ALF) is a life-threatening condition caused by rapid hepatocyte death and impaired liver regeneration. Here we show that extracellular vesicles engineered to express Signal Regulatory Protein Alpha (SIRP-EVs), produced via a scalable 3D bioreactor process with high yield and purity, exhibit significant therapeutic potential by targeting damaged cells and promoting tissue repair. SIRP-EVs block CD47, a crucial inhibitory signal on necroptotic cells, to enhance macrophage-mediated clearance of dying hepatocytes. They also deliver regenerative cargo from mesenchymal stem cells, reprogramming macrophages to support liver regeneration. In male animal models, SIRP-EVs significantly reduce liver injury markers and improve survival, demonstrating their dual-function therapeutic efficacy. By integrating the resolution of necroptosis with regenerative macrophage reprogramming, SIRP-EVs represent a promising platform for restoring liver function. These findings support the development of EV-based in vivo macrophage reprogramming therapies for ALF and other inflammation-driven diseases, paving the way for the clinical application of engineered EV therapeutics.

Microwave ablation (MWA) triggers a weak systemic immune response that leads to the abscopal regression of distant metastases while killing local tumors, known as the abscopal effect. Combining MWA with chimeric antigen receptor (CAR)-T cells demonstrates promise in enhancing the abscopal effect in antigen-homogeneous tumors. However, the loss of the antigen recognized by CAR or intrinsic antigenic heterogeneity in solid tumors poses a major obstacle. SIRPα variant (CV1)-secreting CAR-T (sCAR-T) cells elicit an abscopal effect on distant tumors with antigen heterogeneity in mice receiving local MWA. Mechanistically, sCAR-T cells can locally eliminate antigen-positive tumors and secrete CV1, whereas the secreted CV1 can activate macrophages that migrate to non-ablated tumor sites in response to post-MWA chemokines, eliciting a macrophage-dependent abscopal effect that enables phagocytosis of antigen-heterogeneous cancer cells. This macrophage-dependent abscopal effect instigated by MWA and sCAR-T cells offers a clinically translatable strategy in metastatic solid tumors with antigen heterogeneity.

New breast cancer (BC) diagnoses will soon reach 2.5-3 million/year worldwide, with 15-25% of them being triple-negative breast cancer (TNBC), the most aggressive type, characterized for lacking the main pharmacological targets: estrogen and progesterone receptors (ERs and PRs), as well as HER2 overexpression. Therefore, chemotherapy remains the almost-unique systemic treatment for TNBC. However, some targeted therapies are recommended for use in combination with chemotherapy; namely, PARP inhibitors for BRCA-mutated TNBC, the immune checkpoint inhibitors pembrolizumab and atezolizumab, as well as the antibody-drug conjugates sacituzumab govitecan and trastuzumab deruxtecan, the latter for HER2low subtypes. Regardless of the limited benefits they provide, other treatments with similar mechanisms of action are being investigated in advanced clinical stages. Further, therapies that benefit other cancers, like PI3K/Akt/mTOR pathway and CDK4/6 inhibitors, are still being investigated for TNBC, although convincing results have not been obtained. Given this scenario, it might appear innovation for TNBC treatments has become stuck. However, the huge unmet medical need drives intense research into the biology of the disease. As a result, emerging disruptive therapies are being tested in early-stage trials, designed for novel targets and applying cutting-edge advances in immunotherapy and precision oncology.

Appendiceal mucinous neoplasms (AMN) are rare tumors of the gastrointestinal tract. They metastasize with widespread abdominal dissemination leading to pseudomyxoma peritonei (PMP), a disease with poor prognosis. There are many unknowns about the cellular features of origin, differentiation and progression of AMN and PMP.

We characterized AMNs, PMPs and matched normal tissues using single-cell RNA-sequencing. We validated our findings with immunohistochemistry, mass spectrometry on malignant ascites from PMP patients and gene expression data from an independent set of PMP tumors.

We identified previously undescribed cellular features and heterogeneity in AMN and PMP tumors. There were gene expression signatures specific to the tumor epithelial cells among AMN and PMP. These signatures included genes indicative of goblet cell differentiation and elevated mucin gene expression. Metastatic PMP cells had a distinct gene expression signature with increased lipid metabolism, inflammatory, JAK-STAT and RAS signaling pathway among others. We observed clonal heterogeneity in a single PMP tumor as well as PMP metastases from the same patient.

Our study defined tumor cell gene signatures of AMN and PMP, successfully overcoming challenges of low cellularity and mucinous composition of these tumors. These gene expression signatures provide insights on tumor origin and differentiation, together with the identification of novel treatment targets. The heterogeneity observed within an individual tumor and between different tumors from the same patient, represents a potential source of treatment resistance.

Multiple strategies have been clinically employed as combination partners to enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Although these combinations have demonstrated improved effectiveness in some instances, each presents its own limitations. Autophagy-targeting therapy offers several advantages when combined with ICIs, including enhanced tumor immunogenicity, reduced side effects, and broader applicability to diverse patient populations. However, emerging evidence reveals complex reciprocal regulation between autophagy and immune checkpoints which may complicate combination treatments targeting these two systems. This review focuses on the reciprocal interplay between autophagy and immune checkpoints, and provides valuable guidelines for the determination and adjustment of therapeutic regimens in the future.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1β, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.

CD47 is an immune checkpoint widely regarded as a 'don't eat me' signal. CD47-based anti-cancer therapy has received considerable attention, with a significant number of clinical trials conducted. While anti-cancer therapies based on CD47 remain a focal point of interest among researchers, it is noteworthy that an increasing number of studies have found that CD47-based therapy ameliorated the pathological status of non-cancer diseases. This review aims to provide an overview of the recent progress in comprehending the role of CD47-based therapy in non-cancer diseases, including diseases of the circulatory system, nervous system, digestive system, and so on. Furthermore, we sought to delineate the promising mechanisms of CD47-based therapy in treating non-cancer diseases. Our findings suggest that CD47-based agents may exert their effect by regulating phagocytosis, regulating T cells, dendritic cells, and neutrophils, and regulating the secretion of cytokines and chemokines. Additionally, we put forward the orientation of further research to bring to light the potential of CD47 and its binding partners as a target in non-cancer diseases.

Immunotherapy has demonstrated promise as a treatment for acute myeloid leukemia (AML). However, there is still an urgent need to identify new molecules that inhibit the immune response to AML. Most prior research in this area has focused on protein-protein interaction interfaces. While carbohydrates also regulate immune recognition, the role of cell-surface glycans in driving AML immune evasion is comparatively understudied. The Siglecs, for example, are an important family of inhibitory, glycan-binding signaling receptors that have emerged as prime targets for cancer immunotherapy in recent years. In this study, we find that AML cells express ligands for the receptor Siglec-9 at high levels. Integrated CRISPR genomic screening and clinical bioinformatic analysis identified ST3GAL4 as a potential driver of Siglec-9 ligand expression in AML. Depletion of ST3GAL4 by CRISPR-Cas9 knockout (KO) dramatically reduced the expression of Siglec-9 ligands in AML cells. Mass spectrometry analysis of cell-surface glycosylation in ST3GAL4 KO cells revealed that Siglec-9 primarily binds N-linked sialoglycans on these cell types. Finally, we found that ST3GAL4 KO enhanced the sensitivity of AML cells to phagocytosis by Siglec-9-expressing macrophages. This work reveals a novel axis of immune evasion and implicates ST3GAL4 as a possible target for  immunotherapy in AML.

Anti-tumor immunotherapy was rediscovered and rejuvenated in the last two decades with the discovery of CTLA-4, PD-1 and PD-L1 and the roles in inhibiting immune function and tumor evasion of anti-tumor immune response. Following the approval of the first checkpoint inhibitor ipilimumab against CTLA-4 in melanoma in 2011, there has been a rapid development of tumor immunotherapy. Furthermore, additional positive and negative molecules among the T-cell regulatory systems have been identified that that function to fine tune the stimulatory or inhibitory immune cells and modulate their functions (checkpoint modulators). Many strategies are being explored to target macrophages, NK-cells, cytotoxic T-cells, fibroblasts, endothelial cells, cytokines and molecules involved in tumor tolerance and microbiome. Similar to agents that target checkpoint modulators, these newer targets have the potential to synergize with other classes of immunotherapeutic agents and importantly may overcome the resistance to other immunotherapies. In order to better understand the mechanism of action of all major classes of immunotherapy, design clinical trials taking advantage of different types of immunotherapeutic agents and use them rationally in clinical practice either in combination or in sequence, we propose the group all immunotherapies into three generations: with CTLA-4, PD-1 and PD-L1 inhibitors as the first generation, agents that target the checkpoint modulators as the second generation, while those that target TME as the third generation. This review discusses all three generations of immunotherapy in oncology, their mechanism of actions, major clinical trial results and indication, strategies for future clinical trial designs and rational clinical applications.

Gastrointestinal (GI) cancers are prevalent globally, with leading incidence and mortality rates among malignant tumors. Despite notable advancements in surgical resection, radiotherapy, and chemotherapy, the overall survival rates remain low. Hence, it is imperative to explore alternative approaches that enhance patient outcomes. Cluster of differentiation 47 (CD47), serving as an early diagnostic marker, is predominantly overexpressed in GI cancers and associated with poor prognosis. Targeting the CD47-signal regulatory protein alpha (SIRPα) signaling pathway may provide a novel strategy for GI cancers treatment. This study summarizes current knowledge of the structure and function of CD47 and SIRPα, their roles in signaling pathways, the prognostic significance of CD47, therapeutic strategies targeting the CD47-SIRPα signaling pathway in GI cancer, and highlights key issues for future investigations.

Immunotherapy is an emerging strategy in cancer therapeutics aimed at modulating the immune system to inhibit pro-tumor pathways and increase a tumor's sensitivity to chemotherapy. Several clinically approved immunotherapy treatments, such as monoclonal antibody treatments, have been successful in solid tumors such as breast, colorectal, and pancreatic. However, an outstanding challenge of these strategies is tumor cell resistance. One target of interest for immune cell modulation is targeting macrophages that enter the tumor microenvironment. More specifically, an immune checkpoint of interest is CD47. CD47 is a transmembrane protein that inhibits phagocytic activity by acting as a "don't eat me" signal. In both mice and humans, healthy cells can express CD47, while solid malignancies like colorectal and breast cancer express it most strongly.

Analysis of literature data on the physiological and functional roles of tissue-resident macrophages, along with the structure and mechanisms of action of the CD47 pathway was explored. We also explored how CD47 can influence different aspects of the tumor microenvironment (i.e. cellular metabolism and hypoxia) in addition to current clinical strategies and challenges associated with targeting CD47.

Overall, it was discovered that CD47 is overexpressed in a variety of cancer types in addition to normal tissue, making it a promising treatment regimen to enhance the capability of macrophages to phagocytose tumor cells. However, treatment efficacy is varied in pre-clinical and clinical models due to various challenges such as off-target effects.

This review emphasizes the diverse functionality of macrophages in normal and cancerous tissue, while also emphasizing the importance of macrophage targeting and their clinical significance.

NK/T-cell lymphoma (NKTCL) is a rare type of non-Hodgkin lymphoma (NHL). Although L-asparaginase-based chemotherapy has significantly improved survival in early-stage patients, the prognosis is poor in advanced and relapsed or refractory patients. CD47 is a promising target for cancer immunotherapy. However, the expression of CD47 in NKTCL and the antitumor effect and mechanism of the anti-CD47 monoclonal antibody (mAb) AK117 in NKTCL remain unclear. Firstly, the expression level of CD47 protein in NKTCL cells was detected by immunoblot and flow cytometry. Secondly, in order to validate the role of CD47 downregulation in the proliferation, apoptosis, and cell cycle of NKTCL cells, we used shRNA transfection to knock down CD47 expression. We determined the effect of knocking down CD47 and the novel anti-CD47 antibody AK117 on the phagocytosis of NKYS and YTS cells by M2 macrophages in vitro. Finally, we assessed the ability of AK117 to inhibit tumor growth in an NKTCL xenograft model in which YTS cells were engrafted in SCID mice. The results showed that CD47 is relatively highly expressed in NKTCL cells. CD47 knockdown in NKTCL promoted phagocytosis by M2 macrophages in an in vitro coculture assay. The study also demonstrated that anti-CD47 mAb AK117 promoted phagocytosis of NKTCL cells by M2 macrophages. In addition, in vivo experiments showed that the anti-CD47 mAb AK117 significantly inhibited the growth of subcutaneous xenograft tumors in SCID mice compared to the control antibody IgG. Our results indicate that targeting CD47 monoclonal antibodies is a potential therapeutic strategy for NKTCL.

Targeting CD47 for cancer immunotherapy has been studied in many clinical trials for the treatment of patients with advanced tumors. However, this therapeutic approach is often hampered by on-target side effects, physical barriers, and immunosuppressive tumor microenvironment (TME).

To improve therapeutic efficacy while minimizing toxicities, we engineered an oncolytic vaccinia virus (OVV) encoding an anti-CD47 nanobody (OVV-αCD47nb). We demonstrated the specific binding activity of αCD47nb secreted from the virus-infected cells to CD47 and that both secreted αCD47nb and OVV-αCD47nb blocked the "don't eat me" signal of macrophages.

Intratumorally injected OVV-αCD47nb continuously releases the αCD47nb in tumor tissues, thereby conferring superior systemic activity against breast and colon tumor cells and prolonging survival compared with OVV control. Furthermore, treatment with OVV-αCD47nb also remodeled the TME, as shown by increased T cell infiltration, CD8+ T cell activation and tumor-associated macrophages polarization, significantly enhancing innate and adoptive immunity. Additionally, the inclusion of programmed cell death protein-1 inhibiting boosted the anticancer efficacy of OVV-αCD47nb and raised the full response rate in tumor-bearing animals.

Overall, our findings highlight the therapeutic potential of OVV-αCD47nb for breast and colon cancer, and demonstrate its ability to modulate the immune cell profiles within tumors. This has established a rationale for further exploring OVV-αCD47nb as a potential therapy in the clinic.

SPP1 + macrophages are among the major phagocytic cells, yet promoting tumor immune evasion and predicting unfavorable prognosis, in various cancer types. Meanwhile, the predictive value of the abundance of SPP1 + macrophages in patients receiving immunotherapy remains debatable, indicating the potential existence of subtypes of SPP1 + macrophages with diverse biological functions.

The single cell RNA sequencing data of myeloid cells integrated from several cancers including esophageal squamous cell carcinoma was analyzed for characterizing the function and cellular interactions of SPP1 + macrophages expressing SIRPα. Multiplexed immunohistochemistry was used to quantify the quantity and spatial distribution of SPP1 + macrophages expressing SIRPα. Kaplan-Meier method was used for survival analysis. In vitro and in vivo studies investigating the function of SPP1 + macrophages were performed.

SPP1 + macrophages possessed a high phagocytic signature and could engulf more tumor cells in vitro and in vivo. SIRPα expression could represent the phagocytic activity of SPP1 + macrophages and delineated subsets of SPP1 + macrophages with different functions. SPP1 + SIRPα + macrophages showed close spatial distance to tumor cells and positively correlated with PD1 + CD8 + T cells. A high abundance of SPP1 + SIRPα + macrophages at baseline corresponded to patients' response to PD-1/PD-L1 inhibitors.

A novel subtype of SPP1 + macrophages expressing SIRPα was identified and their abundance predicted patients' response to PD-1/PD-L1 inhibitors.

Transmembrane integrin-associated protein CD47 functions as a potent innate immunity checkpoint and is upregulated by many types of malignant cells, including melanoma during tumor progression. Binding of CD47 to its target receptor, SIRPα, on myeloid cell lineages leads to the initiation of the downstream signaling cascades that inhibit innate immunity anti-tumor responses. Molecular mechanisms underlying upregulation of CD47 during melanoma progression remain largely unknown. In this report, we performed ATAC-Sequencing on patient-derived melanoma cells, as well as, the analysis of ATAC-Seq datasets covering clinical melanoma samples to demonstrate a significant increase in chromatin accessibility for the CD47 promoter region in comparison to normal cells and tissues. Additionally, profiling of multiple CD47 transcript isoforms established that upregulation of CD47 in malignant cells occurs at the mRNA level. Using chromatin immunoprecipitation (ChIP) approaches along with the analysis of ChIP-Seq cancer datasets, we identified the transcription factor NRF-1 which binds at multiple sites within the proximal CD47 promoter region. In combination with serial deletions of CD47 promoter, we defined the minimal DNA region required for its activation, as well as, specific DNA locations within that region, which are preferentially occupied by NRF-1 in tumor cells.

Disulfidotosis is a newly identified form of cell death associated with tumor response, patient outcomes, and cancer progression. This study aims to identify disulfidptosis-related genes (DiRGs) and their role in osteosarcoma (OS) to predict prognosis and optimize drug therapy for better patient survival. Gene expression matrices and clinical information on OS were obtained from the TARGET and GEO databases. Unsupervised clustering analysis identified two DiRG molecular subgroups with significantly different intratumoral heterogeneity and tumor microenvironment cell infiltrating characteristics in OS. A robust disulfidptosis-related prognostic model using five DiRGs was developed, demonstrating excellent predictive and prognostic power in OS with AUC values of 0.69, 0.78, and 0.85 for 1-, 3-, and 5-year periods, respectively. Investigations into the impact of disulfidoptosis on immune status in OS patients across different risk subgroups revealed that a low immune score and compromised immune status were associated with an unfavorable prognosis for OS patients. INF2 and MEGF10 genes are highly reliable predictors of metastasis among the hub DiRG genes. The validation results indicate a robust correlation between the expression of INF2 and MEGF10 and the severity of malignancy and metastasis in OS. Six drugs targeting osteosarcoma metastasis were identified, with INF2-BP-1-102 and MEGF10-AS703569 showing the best docking scores, indicating their potential to treat OS metastasis effectively. These findings provide valuable insight into improving treatment for OS patients.

The CD47-SIRPα signaling has been acknowledged as a significant immune checkpoint and CD47 blocking has been proved as a potential therapeutic strategy for the treatment of solid tumor. However, the potential application of CAR-T cells secreted antibody fragment simultaneously in solid tumor is rarely explored. In this study, we searched bioinformatic databases and investigated the characteristics of CD47 in solid tumors. Then we consulted bioinformatic databases to design, optimize and construct a novel MsC-CAR which could target MAGE-A1 and self-secrete CD47-scFv. The engineering T cells containing MsC-CAR were transfected, verified and characterized. The tumor-inhibitory role of MsC-CART cells was further determined in vitro and in vivo. The results showed that MsC-CARs were successfully constructed and MsC1-CARs demonstrated the preferable features of recognizing MAGE-A1 and secreting CD47-scFv. Engineering T cells transfecting with MsC1-CAR (MsC1-CART cells) exerted the prominent tumor-inhibitory effectiveness, both in different cancer cell lines and LUAD xenograft tumors. The present data highlighted that MsC1-CART cells elaborately combined the adoptive cellular immunotherapy and immune checkpoint inhibitor therapy, may represent a new direction for the treatment of MAGE-A1 positive solid tumors.

Despite the development of cancer biomarkers and targeted therapies, most cancer patients do not have a specific biomarker directly associated with effective treatment options. We have developed VT1021 that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). Our studies identified CD36 and CD47 as dual biomarkers that can be used as patient stratifying tools and prognostic biomarkers for VT1021 treatment.

High expression of cellular self-activated immunosuppressive molecules and extensive infiltration of suppressive immune cells in the tumor microenvironment are the main factors contributing to glioma's resistance to immunotherapy. Nonetheless, technology to modify the expression of glioma cellular self-molecules through gene editing requires further development. This project advances cell therapy strategies to reverse the immunosuppressive microenvironment of glioma (TIME). Bone marrow-derived mesenchymal stem cells (MSCs) are engineered to express bioactive proteins and demonstrate tumor-homing characteristics upon activation by TGF-β. These MSCs are designed to secrete the anti-tumor immune cytokine IL-12 and the nCD47-SLAMF7 fusion protein, which regulates T-cell activity and macrophage phagocytosis. The engineered MSCs are then injected in situ into the glioma site, circumventing the blood-brain barrier to deliver high local concentrations of bioactive proteins. This approach aims to enhance the M1 polarization of infiltrating macrophages, stimulate macrophage-mediated tumor cell phagocytosis, activate antigen-presenting cells, and promote effector CD8+ T cell infiltration, effectively controlling glioma. Additionally, the engineered MSCs may serve as a universal treatment for other tumors that express TGF-β at high levels. This study proposes a novel treatment strategy for the clinical management of glioma patients.