Introduction

The tumor microenvironment (TME) is a dynamic ecosystem composed of stromal cells, immune infiltrates, vasculature, extracellular matrix (ECM), and soluble signaling factors. It plays a critical role in tumor initiation, progression, and response to therapy. In xenograft models, the TME is partially reconstructed, with murine stromal components supporting human tumor engraftment and growth. While this introduces certain limitations, xenografts remain powerful tools for dissecting how the microenvironment modulates tumor biology and drug efficacy.

Stromal Interactions

Murine fibroblasts and myofibroblasts rapidly colonize xenografts, generating a supportive stromal network. These cells secrete growth factors such as hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-β), which activate bypass signaling pathways in tumor cells. Stromal–tumor interactions can drive resistance to targeted therapies, as demonstrated in xenograft models of colorectal and breast cancer where fibroblast-derived ligands reactivated ERK and PI3K signaling despite pathway inhibition. Stromal heterogeneity also influences tumor invasion, angiogenesis, and metastatic spread.

Angiogenesis and Vascular Remodeling

Tumor growth in xenografts depends on the induction of angiogenesis. Vascular endothelial growth factor (VEGF) secreted by tumor and stromal cells promotes new vessel formation. However, murine vasculature differs from human vasculature in both density and permeability, impacting drug delivery and oxygenation. Anti-angiogenic therapies tested in xenografts demonstrate transient efficacy, but tumors often escape through vessel co-option or alternative angiogenic pathways. These findings emphasize the adaptability of the TME and the necessity of combination therapies targeting multiple pro-angiogenic factors.

Immune Components

Traditional xenografts employ immunodeficient mice, limiting the presence of adaptive immunity. Nevertheless, innate immune elements such as murine macrophages, neutrophils, and natural killer cells remain active and influence tumor growth. In humanized xenografts, reconstitution with human hematopoietic stem cells allows the study of T-cell infiltration, checkpoint inhibitor responses, and tumor–immune interactions. These systems reveal how immune evasion mechanisms, such as PD-L1 upregulation or recruitment of regulatory T cells, undermine therapeutic efficacy.

Extracellular Matrix and Drug Penetration

The ECM provides both structural support and biochemical signaling within the TME. In pancreatic xenografts, dense desmoplastic stroma impedes drug penetration, recapitulating clinical challenges in pancreatic ductal adenocarcinoma. Altered ECM composition also affects integrin-mediated signaling, influencing tumor proliferation and survival. Strategies to remodel the ECM, such as enzymatic degradation or inhibition of fibroblast activation, are actively evaluated in xenograft systems to enhance chemotherapy and immunotherapy delivery.

Therapeutic Response Modulation

The TME profoundly shapes therapeutic response in xenograft studies.

• Chemotherapy: Hypoxic tumor niches reduce drug sensitivity and promote quiescent cell states.
• Targeted Therapy: Stromal and immune-derived factors provide survival cues that bypass oncogene addiction.
• Immunotherapy: Humanized xenografts demonstrate how TME-driven immunosuppression attenuates checkpoint inhibitor efficacy.

These insights underscore the importance of designing therapies that target both tumor cells and their supportive microenvironment.

Future Perspectives

Next-generation xenograft models are incorporating human stroma, vasculature, and immune components to more faithfully replicate the human TME. Advances in 3D bioprinting, microfluidics, and spatial omics are enabling reconstruction of patient-specific microenvironments. Combined with systems biology and AI-based modeling, these approaches promise to reveal actionable vulnerabilities within the TME. Ultimately, xenograft models will continue to be essential for unraveling tumor–microenvironment interactions and designing therapeutic regimens that overcome microenvironment-driven resistance.