Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.

Mesenchymal stromal cells (MSC) are a heterogeneous cell population with self-renewal and the ability to differentiate into different lineages. The novel regulatory role of MSC in both adaptive and innate immune responses got extensive investigation and MSC have been widely used in clinical trials as immunosuppressive agents for autoimmune and inflammatory diseases, including graft-versus-host disease (GVHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), chronic kidney disease, etc. Recent studies have found that MSC exerted their immunomodulation function through secreting extracellular vesicles (EVs), which delivered parent cell cargo to recipient cells without oncogenicity or variability. Since MSC-EVs exhibit most of the properties of MSC and take advantage of their cellular immunomodulatory fuction, MSC-EVs appear to a promising none-cell therapy in various human diseases. In this review, we summarize the pivotal roles of MSC-EVs as agents for immunotherapy in diseases.

Chimeric antigen receptor (CAR)-T cell therapy demonstrates substantial efficacy in various hematological malignancies. However, its application in solid tumors is still limited. Clinical studies report suboptimal outcomes such as reduced cytotoxicity of CAR-T cells and tumor evasion, underscoring the need to address the challenges of sliding cytotoxicity in CAR-T cells. Despite improvements from fourth and next-generation CAR-T cells, new challenges include systemic toxicity from continuously secreted proteins, low productivity, and elevated costs. Recent research targets genetic modifications to boost killing potential, metabolic interventions to hinder tumor progression, and diverse combination strategies to enhance CAR-T cell therapy. Efforts to reduce the duration and cost of CAR-T cell therapy include developing allogenic and in-vivo approaches, promising significant future advancements. Concurrently, innovative technologies and platforms enhance the potential of CAR-T cell therapy to overcome limitations in treating solid tumors. This review explores strategies to optimize CAR-T cell therapies for solid tumors, focusing on enhancing cytotoxicity and overcoming application restrictions. We summarize recent advances in T cell subset selection, CAR-T structural modifications, infiltration enhancement, genetic and metabolic interventions, production optimization, and the integration of novel technologies, presenting therapeutic approaches that could improve CAR-T cell therapy’s efficacy and applicability in solid tumors.

Introduction: Exploring monocytes’ roles within the tumor microenvironment is crucial for crafting targeted cancer treatments.Methods: This study unveils a novel methodology utilizing four 20-color flow cytometry panels for comprehensive peripheral immune system phenotyping, specifically targeting classical, intermediate, and non-classical monocyte subsets. Results: By applying advanced dimensionality reduction techniques like t-distributed stochastic neighbor embedding (tSNE) and FlowSom analysis, we performed an extensive profiling of monocytes, assessing 50 unique cell surface markers related to a wide range of immunological functions, including activation, differentiation, and immune checkpoint regulation. Discussion: This in-depth approach significantly refines the identification of monocyte subsets, directly supporting the development of personalized immunotherapies and enhancing diagnostic precision. Our pioneering panel for monocyte phenotyping marks a substantial leap in understanding monocyte biology, with profound implications for the accuracy of disease diagnostics and the success of checkpoint-inhibitor therapies. Key findings include revealing distinct marker expression patterns linked to tumor progression and providing new avenues for targeted therapeutic interventions.

Although chimeric antigen receptor (CAR)-modified adoptive T cell therapy is a promising immunotherapy for hematological malignancies, the efficacy improvement in relapsed/refractory acute lymphoblastic leukemia (ALL) with extramedullary infiltration and in multiple myeloma (MM) is still warranted. Since C3aR activation can promote the expansion of tumor-killing Th17 cells, we hypothesized that incorporating C3aR as a costimulatory domain would augment the antitumor activity of CAR-T. In this study, we introduced the C3aR domain into a CAR and generated BB-ζ-C3aR CAR-T targeting CD19 or BCMA. These new CAR-T exhibited a potent cytolytic ability to eradicate tumor cells expressing CD19 or BCMA in vitro. When administered intravenously to ALL or MM xenograft mouse models, BB-ζ-C3aR CAR-T reduced the tumor burden and improved the survival rate. Of note, these CAR-T could effectively eradicate subcutaneous CD19⁺ tumor cells, highlighting the therapeutic potential in extramedullary leukemia. Mechanistically, BB-ζ-C3aR CAR-T tended to exhibit a Th17 phenotype favoring tumor killing and suppressed Tregs. In addition, the induction of memory T cell in the BB-ζ-C3aR CAR-T cells indicated their long-term effects. Together, our findings suggest that the application of C3aR costimulation boosts the ability of CAR-T to eradicate aggressive tumor cells via Th17 expansion and memory T cell induction.