Mesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.

Cell–cell adhesion mediated by ICAM-1 and VCAM-1 is critical for T cell activation and leukocyte recruitment to the inflammation site and, therefore, plays an important role in evoking effective immune responses. However, we found that ICAM-1 and VCAM-1 were critical for mesenchymal stem cell (MSC)-mediated immunosuppression. When MSCs were cocultured with T cells in the presence of T cell Ag receptor activation, they significantly upregulated the adhesive capability of T cells due to the increased expression of ICAM-1 and VCAM-1. By comparing the immunosuppressive effect of MSCs toward various subtypes of T cells and the expression of these adhesion molecules, we found that the greater expression of ICAM-1 and VCAM-1 by MSCs, the greater the immunosuppressive capacity that they exhibited. Furthermore, ICAM-1 and VCAM-1 were found to be inducible by the concomitant presence of IFN-γ and inflammatory cytokines (TNF-α or IL-1). Finally, MSC-mediated immunosuppression was significantly reversed in vitro and in vivo when the adhesion molecules were genetically deleted or functionally blocked, which corroborated the importance of cell–cell contact in immunosuppression by MSCs. Taken together, these findings reveal a novel function of adhesion molecules in immunoregulation by MSCs and provide new insights for the clinical studies of antiadhesion therapies in various immune disorders.

The advent of immunotherapy, especially checkpoint inhibitor-based immunotherapy, has provided novel and powerful weapons against cancer. Because only a subset of cancer patients exhibit durable responses, further exploration of the mechanisms underlying the resistance to immunotherapy in the bulk of cancer patients is merited. Such efforts may help to identify which patients could benefit from immune checkpoint blockade. Given the existence of a great number of pathways by which cancer can escape immune surveillance, and the complexity of tumor-immune system interaction, development of various combination therapies, including those that combine with conventional therapies, would be necessary. In this review, we summarize the current understanding of the mechanisms by which resistance to checkpoint blockade immunotherapy occurs, and outline how actionable combination strategies may be derived to improve clinical outcomes for patients.

Cancer immunotherapies that engage immune cells to fight against tumors are proving to be powerful weapons in combating cancer and are becoming increasingly utilized in the clinics. However, for the majority of patients with solid tumors, little or no progress has been seen, presumably due to lack of adequate approaches that can reprogram the local immunosuppressive tumor milieu and thus reinvigorate antitumor immunity. Tumor-associated macrophages (TAMs), which abundantly infiltrate most solid tumors, could contribute to tumor progression by stimulating proliferation, angiogenesis, metastasis, and by providing a barrier against antitumor immunity. Initial TAMs-targeting strategies have shown efficacy across therapeutic modalities and tumor types in both preclinical and clinical studies. TAMs-targeted therapeutic approaches can be roughly divided into those that deplete TAMs and those that modulate TAMs activities. We here reviewed the mechanisms by which macrophages become immunosuppressive and compromise antitumor immunity. TAMs-focused therapeutic strategies are also summarized.