Mesenchymal stromal stem cells (MSCs) are the most widely clinically studied cell type within the scope of both regenerative medicine and cellular immunotherapy, owing to their unique therapeutic benefits. In addition to their complex array of paracrine and cell contact-dependent regenerative mechanisms, they also possess extensive immunomodulatory characteristics, distinctive compared to other stem cell subsets. Their existence and biological significance was first assumed already in 1867 by a German pathologist Julius F. Cohnheim, who suggested the presence of a non-haematopoietic cells within the bone marrow, that can circulate to aid in wound repair and possess a fibroblast-like morphology [1], [2]. Their definitive discovery regarding cellular identity is nevertheless accredited to a Russian scientist Alexander Friedenstein, due to series of informative publications in the 1970 s which revealed MSC's colony-forming capacity, differentiation ability and the potential to form a hematopoietic microenvironment [3], [4].

In the following years, new discoveries began appearing consistently which revealed in more and more detail both the origin of MSCs and their biological characteristics. In the 1990 s, the occurrence of MSCs was shown not to be limited to bone marrow but was found to possess widespread distribution throughout the body and their presence was confirmed in several tissues and organs [5]. To this point there was also enough evidence gathered to conclude, at least theoretically, on the MSC capability to differentiate into various end-stage cellular types of the mesoderm including those of bone, cartilage, tendons, fat, muscle and others [6]. It was also in this seminal paper of Caplan, that the use of MSCs as future, self-cellular therapeutics was proposed for regeneration of damaged tissues. The idea for clinical translation of MSCs was soon realized in 1995, when Lazarus et al. published a report of the first phase I trial of autologous, bone marrow-expanded MSCs that were administered to fifteen patients with various haematological malignancies [7]. No adverse events were observed after MSC injections. This step represented a significant breakthrough in terms of clinical translation of MSCs, confirming both preliminary safety and feasibility. It undoubtedly represented a platform for accelerated interest and research of MSC applicability that resulted in exponential rise in number of MSC-related publications of basic, pre-clinical and clinical research in the decades that followed.

The current applicability of MSCs for clinical purpose is perhaps the most extensive among all other cell and gene therapy platforms. This is true for both the numerous ways in which MSC-based Advanced Therapy Medicinal Products (ATMPs) can be manufactured/manipulated and therefore represent different “drugs”, as well as for the great number of diseases that can potentially be targeted using these various MSC-based ATMPs [8]. In other words, we can no longer think of MSC-based therapies as one type of cellular therapy utilizing one type of ATMP. For instance, cell therapy products based on “wild-type” MSCs rely on their intrinsic biological characteristics, i.e. their innate immunomodulatory and paracrine actions, while on the other hand, MSCs can serve as ideal vehicles for targeted delivery of diverse set of genes and their products. Within this broad therapeutic platform, the genetic modification of MSCs represents an exciting and rapidly evolving field with enormous potential for both regenerative medicine and oncology.

For oncological purposes, MSCs can be genetically modified to deliver a great variety of anti-tumor payloads. These include oncolytic viruses (e.g. ICOVIR5), microRNAs with anti-cancer properties (e.g. miR-124a), tumor-killing molecules (e.g. TNF-related apoptosis-inducing ligand - TRAIL), tumor-suppressing proteins (e.g. bone morphogenetic protein-4) and cytokines. Due to their broad effects on the immune system and key role in anti-cancer immunity, cytokines hold a special place in genetic armament of MSCs. They offer us the opportunity to fundamentally transform cellular therapeutics such as MSCs into highly efficient and controlled immune effector cells, capable of directly inhibiting tumor growth or providing key support to anti-tumor immunity. In recent years, we have witnessed an exponential rise in the number of preclinical and clinical studies exploring the utility of cytokines as cancer therapeutics. The reinvigoration of this field was caused by a general shift in cancer therapy toward combinatorial approaches (e.g. strengthening immune checkpoint inhibition therapy), as well as several technological advances in cytokine formulation and delivery, allowing for their targeted and localized activity. Genetic modification of MSCs represents one such key advancement, which can tick off both these boxes, thereby avoiding general issues associated with systemic cytokine therapy, namely high toxicity and short half-life. In this manner, interleukins (IL) and interferons (IFN) with anti-cancer properties can be successfully incorporated into MSC biology, while simultaneously taking advantage of MSCs tumor-homing potential in addition to utilizing various routes of administration.

Although genetic engineering of MSCs offers numerous pharmacological opportunities to approach cancer therapy, their implementation in well executed clinical trials is still at the beginning, as only recently, a few studies with active or completed status have been registered within Clinicaltrials.org database (accession date 7th March, 2024). In this review, we discuss the importance of this advanced therapeutic approach, focusing on MSC armament using ILs and IFNs, underlying immunological mechanisms, genetic engineering techniques and how MSCs can be best utilized for future development of efficient anti-cancer therapeutic strategies.