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The tumor microenvironment (TME) is the complex, dynamic ecosystem surrounding cancer cells, comprising immune cells, blood vessels, fibroblasts, signaling molecules, and the extracellular matrix. It acts as an active supporter of tumor growth, metastasis, and treatment resistance rather than just a bystander. The TME constantly changes through interactions with the tumor, which can create a hypoxic and acidic environment to foster progression.
The tumor microenvironment is in a constant state of change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.
A tumor's vasculature is important to its growth, as blood vessels deliver oxygen, nutrients, and growth factors to the tumor.[15] Tumors smaller than 1–2 mm in diameter are delivered oxygen and nutrients through passive diffusion. In larger tumors the center becomes too far away from the existing blood supply, leading the tumor microenvironment to become hypoxic and acidic.[16] Angiogenesis is upregulated to feed the cancer cells and is linked to tumor malignancy.
Piñeiro Fernández J, Luddy KA, Harmon C, O'Farrelly C (2019). "Hepatic Tumor Microenvironments and Effects on NK Cell Phenotype and Function". International Journal of Molecular Sciences. 20 (17): 4131. doi:10.3390/ijms20174131. ISSN 1422-0067. PMC 6747260. PMID 31450598.
Advancements in remodeling nanotherapeutics have led to progress in suppressing cancer metastasis and reducing the likelihood of cancer occurrence. Strategies included regulation of hypoxia, angiogenesis, cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), and tumor-associated macrophages. These approaches aimed to improve anti-tumor effects and sensitize other therapies. Nanocarrier vehicles (~20–200 nm in diameter) can transport drugs and other therapeutic molecules. These therapies can be targeted to selectively extravasate through tumor vasculature. These efforts include protein capsids and liposomes.
Durable Material Research Group's Achievements for Immosuppresive Tumor Environment
The Durable Materials Research Team published a paper titled "Metal-Phenol Networks Reverse the Immunosuppressive Tumor Microenvironment through Dual Metabolic Modulation and Immunogenic Cell Death" in the Journal of Controlled Release 2025. (IF 11.5, Q1).
Aerobic glycolysis, the primary metabolic pathway in cancer cells, leads to glucose depletion and the accumulation of immunosuppressive metabolites such as lactate, ultimately limiting the efficacy of existing immunotherapies. In this study, we developed a metal-phenol network (MPN) by coating zinc oxide (ZnO) nanoparticles with epigallocatechin gallate (EGCG) to modulate cancer cell metabolism for tumor microenvironment remodeling and immune activation.
Under acidic conditions, MPN releases Zn2+ ions and EGCG, effectively modulating cancer cell metabolism by inhibiting glycolysis and mitochondrial metabolism. This suggests the potential of combining metabolic therapy and immunotherapy as a novel strategy to overcome the limitations of existing cancer treatments.
Schematic illustration of the mechanism of TME reprogramming MPNs, MPNs are consisted ZnO nanoparticles and EGCG. Upon endocytosis the acidic tumor microenvironment triggers the release of Zn and EGCG. Journal of Controlled Release.
The Durable Materials team published “Local delivery of IL-12 mRNA and indoximod prodrug potentiates antitumor immunity by increasing T cell effector function,” in the Journal of Controlled Release 2025. (IF 11.5, Q1)
Administration of recombinant cytokines, particularly interleukin-12 (IL-12), has promising clinical potential in the treatment of various cancers. Sustained intratumoral delivery of IL-12 can restore resident CD8+ effector T cells within tumors and induce the priming of antitumor CD8+ effector T cells; however, CD8+ T cell-dependent antitumor efficacy is generally transient. In this study, we designed a lipid nanoparticle (LNP) system that could successfully deliver indoximod (IND), an IDO inhibitor, and mRNA encoding IL-12 to upregulate IFNγ-dependent indoleamine 2,3-dioxygenase (IDO) expression. To increase drug loading efficiency, we synthesized an IND prodrug by conjugating IND to cholesterol via an ester bond.
The optimized IND prodrug encapsulated in LNPs was successfully transfected into tumor cells and macrophages, which secreted IL-12 cytokines. Upon IL-12 transfection, macrophages upregulated T cell costimulatory factors and released TNFα cytokines. This suggests that the tumor microenvironment can be changed from a cold tumor to a hot tumor for immunotherapy, and the increased secretion of IL-12 cytokine causes T cells to release high levels of IFNγ, which plays a key role in IL-12-mediated immunotherapy, suggesting a strategy to overcome the limitations of single IL-12 therapy.
Schematic illustration of the research. (A) Varius lipid components including indoximod (IND) prodrug were rapidly mixed with IVT IL-12 mRNA via microfluidic device to form IDO inhibiting LNP. (B) Transfected IL-12 reprograms tumor associated macrophages and activates T cells, eliciting effective anticancer immunity. Schematic illustration was created with BioRender.com, Journal of Controlled Release.
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