Reprogramming the tumor microenvironment with biotechnology

Abstract

The tumor microenvironment (TME) is a unique environment that is developed by the tumor and controlled by tumor-induced interactions with host cells during tumor progression. The TME includes immune cells, which can be classified into two types: tumor- antagonizing and tumor-promoting immune cells. Increasing the tumor treatment responses is associated with the tumor immune microenvironment. Targeting the TME has become a popular topic in research, which includes polarizing macrophage phenotype 2 into macrophage phenotype 1 using Toll-like receptor agonists with cytokines, anti-CD47, and anti-SIPRα. Moreover, inhibiting regulatory T cells through blockades and depletion restricts immunosuppressive cells in the TME. Reprogramming T cell infiltration and T cell exhaustion improves tumor infiltrating lymphocytes, such as CD8⁺ or CD4⁺ T cells. Targeting metabolic pathways, including glucose, lipid, and amino acid metabolisms, can suppress tumor growth by restricting the absorption of nutrients and adenosine triphosphate energy into tumor cells. In conclusion, these TME reprogramming strategies exhibit more effective responses using combination treatments, biomaterials, and nanoparticles. This review highlights how biomaterials and immunotherapy can reprogram TME and improve the immune activity.

Keywords: Biomaterials; Combination treatment; Nanoparticle; Reprogramming; Tumor microenvironment.

Scheme 1

Schematics of various methods of reprogramming the tumor microenvironment

Fig. 1

Schematic of tumor microenvironment reprogramming with biomaterials. a Repolarizing the M2 into the M1, b inhibiting regulatory T cells (Tregs), c reprogramming T cell exhaustion, d enhancing T cell infiltration by reprogramming

Fig. 2

TLR7/8 agonists can decrease tumor growth. a In vivo tumor treatment of Smac-TLR7/8 hydrogels during radiotherapy. Tumor volume curves in general and body weight of different treatment groups. (Reproduced with permission from [29] Copyright 2022, Bioactive Materials). b Expression of CD80 (M1) (upper) and CD206 (M2) (below) in U87 orthotopic glioma of Balbc/nude mice after treatment. Albumin-binding nanoparticles reprogram M2 into M1. (Reproduced with permission from [39] Copyright 2018, Chemical Science)

Fig. 3

TLR2 and TLR3 can convert M2 into M1. a TLR-3 triggering reverts human M2 to M1. The size of the tumor is indicated in squared millimeters at different time points. (Reproduced with permission from [40] Copyright 2018, Frontiers in Immunology). b Cytokine profile of M0-, M1-, and M2-polarized macrophages following TLR ligand exposure and activation. (Reproduced with permission from [43] Copyright 2017, Arthritis Research & Therapy)

Fig. 4

Targeting CD47 and SIRPα with nanoparticles. a 2C8 inhibits tumor growth in xenotransplantation models. Mice were treated with two different doses of 2C8 or Phosphate-buffered saline. The tumor volume of tumors per group is depicted over time. (Reproduced with permission from [53] Copyright 2020, Frontiers in Oncology). b Schematic showing repolarization of M2 to M1 and promoting phagocytosis by blocking the signal in tumor cells by IMD@Hf-DBP/αCD47 and X-ray radiation (Reproduced with permission from [54] Copyright 2020, American Chemical Society)

Fig. 5

Reprogramming of TAM with biomaterials. a A combination of R848, which is a TLR7/8 agonist, and CDNP can decrease the tumor size. (Reproduced with permission from [36] Copyright 2019, Theranostics). b Effect of chitosan nanoparticles on reprogramming of TAMs and tumor metastasis in animals, the mouse acute lung injury model, was established (Reproduced with permission from [46] Copyright 2022, Elsevier). c Growth curves of primary tumors and distant tumors of bilateral CT26 tumor-bearing mice. Black, red, and blue arrows refer to intratumoral injection, X-ray irradiation, and intraperitoneal injection, respectively. (Reproduced with permission from [54] Copyright 2020, American Chemical Society)

Fig. 6

Inhibition and depletion of Tregs in TME can increase the survival rate and decrease tumor growth. a Schematic of the experimental setup to evaluate the contribution of IFN-γ to anti-tumor T cell activity in vivo. Mice bearing orthotopic glioblastoma tumors (GL261-MGH or CT2A, size -2 mm³) were treated with six doses of (i) αPD1 + αGITR, and (iv) αPD1 + αGITR + αIFN-γ (250 μg/mouse). (Reproduced with permission from [68] Copyright 2021, Nature Communication). b CTLA-4 blockade enhances CTL induction in the absence of CD25⁺ Tregs. CD25.⁻ splenocytes were used to analyze the effect of CTLA-4 blockade on the induction of effector CTL in vitro (left) and in vivo (right). (Reproduced with permission from [69] Copyright 2021, Clinical Cancer Research)

Fig. 7

Reprogramming T cell exhaustion with combination therapeutic strategies can increase efficacy. a Efficacy of a single PD-1 blockade and combined blockade of PD-1 and CTLA-4 on the production of effector cytokines from CD8.⁺ TILs. (Reproduced with permission from [92] Copyright 2021, Frontiers in Immunology). b Blocking the Tim-3 and PD-1 signaling pathways restores IFN-γ production. (Reproduced with permission from [89] Copyright 2021, Frontiers in Immunology)