Role of nanotechnology in modulating the tumor microenvironment to enhance immunotherapy efficacy

Table 1 Key tumor microenvironment components, their roles, and therapeutic targets

Component	Role in TME	Therapeutic targets
CAFs	Promote tumor growth, immune evasion, and ECM remodeling	Targeting biglycan, inhibiting CAF signaling pathways, or depleting CAFs
TAMs	Promote tumor progression, angiogenesis, and immune suppression	Targeting the CSF1/CSF1R axis or inhibiting TAM polarization
Tregs	Suppress antitumor immunity and promote tumor growth	Targeting the IL-2/IL-2R axis or inhibiting Treg function
MDSCs	Inhibit T cell function and promote immune suppression	Targeting ARG1 or inhibiting MDSC recruitment
ECM	Acts as a physical barrier and modulates immune cell function	Targeting ECM components such as collagen or hyaluronan
Cytokines	Regulate immune cell function and promote immune evasion	Targeting TGF-β signaling or enhancing proinflammatory cytokines
Hypoxic conditions	Promote immune suppression and tumor progression	Targeting HIF signaling, enhancing oxygenation, or inhibiting adenosine-generating enzymes

TME: Tumor microenvironment; CAFs: Cancer-associated fibroblasts; TAM: Tumor-associated macrophages; HIF: Hypoxia-inducible factor; Tregs: Regulatory T cells; MDSCs: Myeloid-derived suppressor cells; ECM: Extracellular matrix.

Table 2 Summary of nanoparticle designs showing size, surface charge, functional modifications, and their application in targeting key immunosuppressive immune cells such as tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and dendritic cells within the tumor microenvironment

Nanoparticle type	Size (nm)	Surface charge	Surface modification	Payload	Target immune cell (s)	Key effect	Ref.
Polymeric nanocluster (SPN-R848)	Approximately 100	Slightly positive	pH-responsive polymer shell	TLR7/8 agonist (R848)	TAMs, DCs	Polarizes M2 TAMs to M1, activates DCs	[49]
Lipid-coated CaCO3 NPs (CaGlu)	Approximately 150	Neutral	β-glucan surface	Calcium carbonate + β-glucan	TAMs, Tregs	Repolarizes TAMs, suppresses Tregs	[50]
Biomimetic dendritic cell-like NP	Approximately 120	Near neutral	Decorated with anti CD3/CD28/PD-1	Immunomodulatory antibodies	DCs, T cells	Activates DCs, enhances T cell priming	[56]
Iron oxide NP	Approximately 50	Positive	Mannose ligand	Iron core	TAMs	Promotes M1 polarization via ROS generation	[47]
Liposome-based RNAi NP	Approximately 90	Slightly negative	PEGylation, targeting peptide	siRNA targeting IDO/TGF-β	MDSCs, Tregs	Suppresses immunosuppressive pathways	[51]

TAM: Tumor-associated macrophages; Tregs: Regulatory T cells; MDSCs: Myeloid-derived suppressor cells; TGF-β: Transforming growth factor-beta; IDO: Indoleamine-2,3-dioxygenase; NP: Nanoparticle.