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The research aims to explore novel strategies for promoting organ transplant tolerance by targeting innate immune cells.

February 12, 2026Open Access

Innovative approaches targeting innate immune cells to promote organ transplant tolerance

CTChiyoshi ToyamaThomas University ATAW ThomsonUniversity of Pittsburgh

Key Points

The research aims to explore novel strategies for promoting organ transplant tolerance by targeting innate immune cells.
Review of recent advances in innate immune cell modulation
Discussion of myeloid inhibitory checkpoints and their role in tolerance
Examination of metabolic reprogramming techniques using mTOR inhibitors
Evaluation of CRISPR/Cas9 gene editing in T cell regulation
Analysis of regulatory myeloid cell transfer in transplant scenarios
Identification of specific innate immune cell subsets that regulate allograft outcomes
Demonstrated potential of mTORi-loaded nanoparticles to modulate immunity
Showed CRISPR/Cas9 can effectively silence costimulatory signals in T cells
Highlighted adoptive transfer of donor-derived regulatory cells improves transplant tolerance
Proposed strategies indicate a paradigm shift in achieving long-term allograft survival

Abstract

Achieving long-term allograft survival while minimizing systemic immunosuppression (IS) remains a critical unmet need in transplantation. While adaptive immunity has traditionally been the primary focus of IS therapy, innate immune cells—that include neutrophils, monocytes, macrophages, dendritic cells, myeloid-derived suppressor cells, innate lymphoid cells (ILCs), natural killer (NK) cells, and gamma delta (γδ) T cells act as key upstream orchestrators of allograft rejection and tolerance. Recent advances in single-cell RNA sequencing and spatial transcriptomics have unveiled the profound heterogeneity of these cell populations, identifying distinct regulatory subsets and novel inhibitory checkpoints. These high-resolution insights provide the scientific rationale for developing innovative precision therapies that can selectively modulate innate immune reactivity without compromising global immunity. Here, we review innovative strategies to target/amplify these mechanisms, including targeting the myeloid inhibitory checkpoints (e.g., leukocyte immunoglobulin-like receptor B; sialic acid-binding immunoglobulin-like lectin-E) to induce tolerogenic phenotypes. We further discuss the modulation of metabolic reprogramming to prevent “trained immunity” using mammalian target of rapamycin inhibitor (mTORi)-loaded nanoparticles, and the use of CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing to silence T cell costimulatory signals. We evaluate the adoptive transfer of regulatory myeloid cells, -specifically donor-derived regulatory macrophages and regulatory dendritic cells, and innate lymphoid cells in transplant recipients. Furthermore, the potential of targeting specific NK cell and ILC subsets associated with graft regulation is addressed. Collectively, these emerging approaches aim to reprogram the allograft microenvironment, offering a promising paradigm shift towards establishing transplant tolerance.

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