The formation of an immunosuppressive tumor microenvironment (TME) impairs natural killer (NK) cell infiltration and persistence within tumor tissue and significantly diminishes NK-mediated cytotoxicity. This presents a substantial barrier to the efficacy of NK cell therapy in solid tumors. Current strategies aim to overcome immune evasion by enhancing NK cell recognition and cytotoxicity, while promoting their persistence, infiltration, and resistance to the TME. This review focusses on the biophysical characteristics of TME and specific components of the extracellular matrix (ECM) that affect NK cell activity, with the goal of identifying therapeutic approaches to modulate the TME and create a supportive niche for adaptive immune cell function. Advancements in interdisciplinary collaborations integrating oncology, cell biology, physics, engineering, materials science, and nanotechnology are crucial in advancing therapeutic strategies targeting ECM rigidity and mechanotransduction signaling pathways.

Regeneration of periodontal tissues requires an integrated approach to the restoration of the periodontal ligament, cementum, and alveolar bone surrounding the teeth. Current strategies in endogenous regenerative dentistry widely use biomaterials, in particular the decellularized extracellular matrix (dECM), to facilitate the recruitment of populations of resident cells into damaged tissues and stimulate their proliferation and differentiation. The purpose of our study was to evaluate the effect of the exogenous components of the extracellular matrix (hyaluronic acid, laminin, fibronectin) on the differentiation of periodontal ligament stem cells (PDLSCs) cultured with dECM (combinations of decellularized tooth matrices and periodontal ligament) in a 3D collagen I hydrogel. The immunohistochemical expression of various markers in PDLSCs was assessed quantitatively and semi-quantitatively on paraffin sections. The results showed that PDLSCs cultured under these conditions for 14 days exhibited phenotypic characteristics consistent with osteoblast-like and odontoblast-like cells. This potential has been demonstrated by the expression of osteogenic differentiation markers (OC, OPN, ALP) and odontogenic markers (DSPP). This phenomenon corresponds to the in vivo state of the periodontal ligament, in which cells at the interface between bone and cementum tend to differentiate into osteoblasts or cementoblasts. The addition of fibronectin to the dECM most effectively induces the differentiation of PDLSCs into osteoblast-like and odontoblast-like cells under 3D culture conditions. Therefore, this bioengineered construct has a high potential for future use in periodontal tissue regeneration.

An approach called cell-free therapy has rapidly developed in regenerative medicine over the past decade. Understanding the molecular mechanisms and signaling pathways involved in the internal potential of tissue repair inspires the development of new strategies aimed at controlling and enhancing these processes during regeneration. The use of stem cell mobilization, or homing for regeneration based on endogenous healing mechanisms, prompted a new concept in regenerative medicine: endogenous regenerative medicine. The application of cell-free therapeutic agents leading to the recruitment/homing of endogenous stem cells has advantages in overcoming the limitations and risks associated with cell therapy. In this review, we discuss the potential of cell-free products such as the decellularized extracellular matrix, growth factors, extracellular vesicles and miRNAs in endogenous bone and dental regeneration.