Cellular therapy is transitioning from proof-of-concept biology to a scalable, programmable drug modality, with mesenchymal stromal/stem cells (MSCs) and natural killer (NK) cells at the forefront of this transformation. Leveraging their immune-privileged properties and context-dependent immunomodulatory functions, MSCs have pioneered the modern paradigm of allogeneic, off-the-shelf cellular therapies. Clinically, allogeneic MSCs have been used successfully across HLA barriers to treat steroid-refractory acute GvHD (Le Blanc et al., 2008), consolidating their role as a scalable, off-the-shelf immunomodulatory platform.

In contrast, NK cells recognise target cells through the balance of activating and inhibitory receptors, rather than relying on antigen-specific TCR binding, which enables their safe allogeneic use. Ruggeri et al. (2002) demonstrated in haploidentical haematopoietic stem cell transplantation that alloreactivity derived from donor-derived NK cells enhances the graft-versus-leukaemia (GVL) effect without increasing the risk of graft-versus-host disease (GvHD). This finding established the intrinsic compatibility of NK cells with allogeneic immunotherapy.

However, a growing body of mechanistic and translational research indicates that MSCs and NK cells not only co-exist within the therapeutic ecosystem—they form a biologically significant axis for immune calibration and precise cytotoxicity regulation. Their interaction is not merely antagonistic (i.e., MSC-mediated inhibition versus NK cell-mediated lysis of MSCs) but is context-sensitive, programmable, and potentially synergistic. For leaders in biopharmaceutical R&D, the core question is no longer whether each cell type is effective individually, but how to rationally design them to work in concert.

I. Beyond Oncology: MSC–NK Synergy in Ageing and Senotherapy

The value of MSC–NK synergy extends far beyond oncology. Ageing is characterised by two intertwined hallmarks: stem cell exhaustion and immunosenescence. The biology of MSCs and NK cells converges directly in this domain, presenting a highly promising intervention target.

1. The Dual Hallmarks of Ageing: Why Combination Intervention is Needed

As age increases, two key changes occur in the human body:

• Accumulation of Senescent Cells (SNCs): These cells no longer divide but continuously secrete pro-inflammatory factors, growth factors, and matrix-remodelling enzymes, forming the Senescence-Associated Secretory Phenotype (SASP). SASP drives chronic low-grade inflammation ("inflammaging"), damages the tissue microenvironment, and promotes fibrosis and cancer.
• Decline in Stem Cell Function: The number and function of various adult stem cells, including MSCs, decrease, leading to compromised tissue regeneration capacity.

Deng & Terunuma (2024) pointed out that these two processes reinforce each other: SASP accelerates stem cell ageing, while stem cell depletion reduces the capacity to clear senescent cells, forming a vicious cycle (Deng & Terunuma, 2024). Single intervention strategies often struggle to break this cycle, providing the rationale for MSC–NK combination therapy.

2. NK Cells as Senolytic Agents

NK cells are the body's natural "senescent cell cleaners." They recognise stress ligands (such as MICA, MICB, and the ULBP family) up-regulated on the surface of senescent cells and eliminate them by releasing granzymes and perforin.

Deng & Terunuma (2024) emphasise that adoptive NK cell therapy represents a potential life-extending intervention (Deng & Terunuma, 2024):

• NK cells clear senescent cells (SNCs), directly reducing the source of SASP.
• They lower systemic chronic inflammation levels.
• They restore immune surveillance function, reducing the risk of age-related cancers.
• They improve the tissue microenvironment, indirectly supporting stem cell function.

However, in aged individuals, NK cells themselves face functional decline—termed NK cell senescence, characterised by decreased cytotoxicity, reduced cytokine secretion, and lower expression of activating receptors.

Figure 1 NK clears senescent cells to lower SASP

Source: Deng et. al. (2024)

Note. Adapted from “Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics”, by Deng et. al. (2024).

3. MSCs and Immunosenescence

Ageing also impairs MSC function. Fraile et al. (2022) systematically described this process and explored strategies to counteract MSC senescence (Fraile et al., 2022):

• Reduced Regenerative Capacity: The proliferative potential and differentiation ability of senescent MSCs are significantly diminished.
• Altered Immunomodulatory Profile: Secretion of anti-inflammatory factors decreases, while the pro-inflammatory tendency increases.
• Increased Senescence Burden: MSCs themselves become a source of senescent cells, further deteriorating the microenvironment.

However, supplementing with young, healthy MSCs can reverse this trend. Numerous studies confirm that MSC therapy can:

• Reduce systemic inflammation by secreting factors like PGE₂ and IL-10.
• Improve tissue regeneration by activating endogenous stem/progenitor cells through paracrine effects.
• Regulate immunosenescence by reshaping the body's immune cell repertoire and restoring immune homeostasis.

Wang et al. (2023, 2025) systematically summarised the clinical application potential and challenges of MSCs in the field of immunosenescence in their reviews, providing a theoretical basis for MSCs as an anti-ageing intervention (Wang et al., 2023; Wang et al., 2025). Li et al. (2025) further expanded on the application of MSCs and their exosomes in age-related diseases, including osteoporosis, neurodegenerative diseases, and immune dysfunction (Li et al., 2025).

II. Clinical Translation Landscape: From Proof-of-Concept to Rational Design

Direct clinical trials of co-infusion of MSCs and NK cells remain limited (as of 2025). However, with the clinical establishment of MSC therapies in inflammatory diseases, the rapid advancement of NK therapies in oncology, and robust preclinical validation of engineered MSC–NK complexes in oncology and ageing, a clear trend is emerging: the next wave of cell therapies may no longer be single-cell-type products but engineered cellular ecosystems.

For translational projects aiming to advance MSC–NK combination therapies, current research progress offers three rational design models.

Model 1: Sequential Immune Clearance and Tissue Repair

Applying MSC–NK synergy in the anti-ageing field theoretically addresses both core hallmarks of ageing simultaneously. The core logic of this model is the dual mechanism of "clearance + reconstruction." The essence lies in "clearing first, then rebuilding."

In states of chronic inflammation or immune dysregulation, microenvironmental instability limits the effectiveness of regulatory cells. In such cases, initially using NK cells for "battlefield clearance"—removing senescent cells and reducing inflammatory burden—followed by MSC infusion for "ecological reconstruction"—improving the microenvironment and supporting tissue repair—often achieves better synergistic effects.

NK cells are responsible for "clearance"—eliminating senescent cells and dysfunctional immune cells, breaking the chronic inflammation cycle driven by SASP.

MSCs are responsible for "reconstruction"—rebuilding the regenerative cellular microenvironment and restoring tissue repair capacity.

Through this synergy, MSC-NK combination therapy holds the potential for systemic-level intervention in the ageing process, rather than merely delaying a single age-related pathology.

Model 2: MSCs as a Support Platform for NK Cells

In this model, MSCs are engineered to provide comprehensive functional support for NK cells. This strategy transforms MSCs into programmable stromal scaffolds, with the core goal of enhancing the persistence and functional activity of NK cells in vivo.

This "empowering" combination is particularly important when NK cells themselves are functionally impaired (e.g., in aged individuals) or face an inhibitory microenvironment.

Specific aspects include:

• Survival Signals: By expressing key cytokines like IL-15, MSCs maintain the in vivo survival and proliferation of NK cells.
• Recruitment Signals: By secreting chemokines like CXCL9/CXCL10, MSCs leverage their homing capacity to guide NK cells to sites of senescence or inflammation.
• Metabolic Support: Provide the metabolic substrates and microenvironmental nutrients necessary for NK cell function.

Model 3: Integration of Microenvironment Reprogramming and Precision Clearance

This is the most complex synergy model, centred on functional specialisation and spatiotemporal coordination. It involves first reducing pathological inflammation levels via MSC infusion to create a favourable microenvironment for subsequent effector cells, followed by NK cell infusion to execute precise cytotoxic clearance.

• Role of MSCs: Reshape the local immune microenvironment, including modulating macrophage polarization (from pro-inflammatory M1 to anti-inflammatory M2) and adjusting cytokine profiles.
• Role of NK Cells: Execute precise cytotoxic clearance targeting senescent or diseased cells within this optimised environment.

This strategy is particularly suitable for scenarios such as:

• Post-Transplant Relapse Prevention: Using MSCs first to control GvHD risk and regulate immune homeostasis, followed by NK cells to clear residual leukaemia cells.
• Solid Tumours with Significant Inflammatory Infiltration: Leveraging the anti-inflammatory properties of MSCs to "cool" the tumour microenvironment before enabling NK cell-mediated killing.

This dual-pronged approach integrates immunomodulation with immune clearance, enabling systemic intervention in complex pathological processes. 

III. Rational Perspective on Sequential Strategies: Sequence is a Tactic, Status is the Foundation

In translating MSC–NK sequential strategies to clinical application, a key point warrants emphasis: not all populations require combination therapy or a fixed sequence. A scientific approach must be grounded in individual biological status rather than standardised protocols.

Key considerations include:

• Dose ratio between MSCs and NK cells
• Administration timing and sequencing
• Biomarkers for interaction dynamics
• Regulatory strategy for combination biologics
• Development of advanced potency assays

It is crucial to emphasise that these are not speculative concepts. Both MSCs and NK cells have been independently validated in human clinical trials. The challenge is no longer feasibility, but integration.

IV. From Scientific Concept to Industrial Practice: We Need "Twin Engine" Drive

The synergy between MSCs and NK cells represents a methodological evolution in cell therapy—from single-function interventions to multi-cellular, system-level strategies. By integrating MSCs' roles in navigation and support with NK cells' cytotoxic precision, this approach reflects a paradigm shift towards coordinated therapeutic design.

However, such innovation also demands advanced industrial capabilities. Scalable, standardised, and high-quality cell manufacturing systems are essential to bring these strategies into clinical practice.

This integration of biological insight with industrial technology is critical to ensuring that MSC–NK synergy can transition from conceptual promise to tangible patient benefit.

Conclusion

The combination of NK cells and mesenchymal stem cells represents a strategic framework rather than a universal solution. In certain populations, sequential modulation of immune function followed by sustained microenvironmental support may yield improved outcomes

However, the most appropriate approach is inherently individualised. Therapeutic strategies must consider age, physiological condition, and clinical context. Cellular therapies are not rapid interventions; meaningful biological change occurs gradually.

A rational understanding of timing, combination, and patient-specific factors remains more important than the indiscriminate application of synergistic strategies.

References

Blanc, K. L., Frassoni, F., Ball, L., Locatelli, F., Roelofs, H., Lewis, I., Lanino, E., Sundberg, B., Bernardo, M. E., Remberger, M., Dini, G., Egeler, R. M., Bacigalupo, A., Fibbe, W., & Ringdén, O. (2008). Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. The Lancet, 371(9624), 1579–1586. https://doi.org/10.1016/s0140-6736(08)60690-x

Deng, X., & Terunuma, H. (2024). Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics. Immunity & Ageing, 21(1), 43. https://doi.org/10.1186/s12979-024-00451-2

Li, H., & Bai, L. (2025). Advances in mesenchymal stem cell and exosome-based therapies for aging and age-related diseases. Stem Cell Research & Therapy, 16(1), 401. https://doi.org/10.1186/s13287-025-04318-1

Ruggeri, L., Capanni, M., Urbani, E., Perruccio, K., Shlomchik, W. D., Tosti, A., Posati, S., Rogaia, D., Frassoni, F., Aversa, F., Martelli, M. F., & Velardi, A. (2002). Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science, 295(5562), 2097–2100. https://doi.org/10.1126/science.1068440

Wang, X., Guo, D., He, C., Wang, X., Wei, Y., Zhang, F., Wang, L., & Yang, Y. (2025). Clinical application of mesenchymal stem cells in immunosenescence: a qualitative review of their potential and challenges. Stem Cell Research & Therapy, 16(1), 265. https://doi.org/10.1186/s13287-025-04360-z

Wang, Y., Gao, T., & Wang, B. (2023). Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Research & Therapy, 14(1), 260. https://doi.org/10.1186/s13287-023-03497-z