Engineered MSCs enable bone marrow-targeted immunomodulation

Abstract

Tumors are increasingly recognized as a consequence of systemic immune dysregulation, while current therapies merely focus on direct tumor killing or local immune activation, overlooking the systemic immune landscape that enables tumorigenesis and metastasis. Targeting distal immune organs, such as the bone marrow (BM), without perturbing tumors remains challenging. Here, we develop a BM-targeted and tumor-evasive cell vector that restricts immunomodulation to the BM niche, enabling systemic immune reprogramming through niche-derived signaling. This mesenchymal stem cell (MSC)-based vector overexpresses Golgi apparatus protein 1 (MSC^Glg1) to mimic BM affinity signals. In a myelosuppression model, MSC^Glg1 delivers CDK4/6 inhibitors (CDK4/6i) to protect hematopoietic stem and progenitor cells (HSPCs) from chemotherapy toxicity while preserving antitumor efficacy. In a subcutaneous tumor model, MSC^Glg1 delivers interleukin-7 (IL-7), restoring immune competence without promoting tumor proliferation. This strategy establishes a versatile framework for targeted immunomodulation to treat cancer as a systemic immune disease.

Keywords: BM targeting; MSCs; bone marrow; bone marrow protection; drug delivery; immune therapy; mesenchymal stromal cells; metastatic organotropism; tumor evasion.