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have been designed to modulate tumor microenvironments. Recent advances in nanotechnology has been shown to facilitate the efficient regeneration of innate immunity by
delivering immunostimulatory molecules or immunosuppressive inhibitors or selfstimulating innate immune cells. We highlighted how NPs can be harnessed to augment
the function of innate immune responses and augment adaptive immunity.
4.1 Macrophage polarization
Tumor-associated macrophages (TAMs) are a key component of tumor microenvironments that create immunosuppressive surroundings to activate tumor proliferation,
angiogenesis, and metastasis [61,62]. Several environmental factors such as fibrosis, hypoxia, nutrient availability, and lymphocyte-derived factors reeducate macrophage phenotype to antiinflammatory M2 macrophage, thus supporting tumor progression
[61,62]. Clinically, TAMs diminish anticancer responses implemented by conventional
cancer treatments via orchestration of tumor-promoting activity to damaged tissues or
cells [61,62]. TAM-mediated immunosuppressive microenvironments directly affected
the activation of APCs and cytotoxic T cell responses whereas the population of Tregs
is considerably expanded by immunosuppressive cytokines, IL-10 and TGF-β, resulting
in limited effectiveness of cancer immunotherapy [61,62]. To reprogram tumor micro-
environments, a variety of approaches for macrophage polarization have been widely
investigated by delivering immunostimulatory agents or self-stimulating inflammatory
signaling pathways [61,62]. We will discuss how various NPs reeducate TAMs to elicit
enhanced antitumor immune responses.
Delivering immunostimulatory molecules to TAMs is the most straightforward strategy
to polarize TAMs to M1 phenotype, thus recruiting cytotoxic T cell responses (Fig. 4). In
one example, the delivery of TLR-7/8 agonists with nanotechnology allowed for successful macrophage reeducation to ameliorate the potency of cancer immunotherapy [63].
217Challenges and opportunities of nanotechnology in cancer immunotherapy
Fig. 4 Various NPs can reeducate M2 macrophages with M1 mode, thus activating DCs, NK cells, and
T cells along with suppressing Treg activity to induce antitumor effect.
218 DaeYong Lee et al.
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First, numerous immunostimulatory candidates were screened to find the optimal agent
that was capable of polarizing macrophage phenotype [63]. Then, R848 molecules,
TLR-7/8 agonist, were loaded using cross-linked β-cyclodextrin via host-guest interactions to efficiently and specifically deliver the cargos into macrophages [63]. The
β-cyclodextrin moiety of the NPs rendered accumulation in tumor tissues, and TAMs
retarded the shift M2 to M1 mode by secreting IL-12 [63]. The cotreatment of the
NPs and PD-1 antibody dramatically reduced tumor volume and extended the survival
period [63].
The proinflammatory cytokine delivery to TAMs is also a well-defined method to
reprogram macrophage phenotype [64]. To be exemplified, PEG-imidazoylated poly
(β-aminoester) was synthesized to encapsulate IL-12 and self-assemble into NPs [64].
The NP-mediated IL-12 delivery shifted TAMs to M1 phenotype by increasing
CD107 expression along with reducing CD206 expression as M2 markers [64]. Moreover, the in vivo study showed that IL-12 delivery to tumor modulated tumor microenvironments and inhibited tumor proliferation, which was associated with the recruitment
of macrophages and CD8
+
T cells into tumor tissues [64]. For the advanced version of
IL-12 delivery, collagen-binding IL-12 was designed by conjugated collagen-binding
peptide sequence to IL-12 to ameliorate the effects of cancer immunotherapy [65].
The strategy of collagen-binding highly accelerated IL-12 accumulation in tumor stroma
as collagen is abnormally exposed in the disordered tumor vasculature [65]. The collagenbinding IL-12 induced the regression of melanoma cancers and prolonged the survival
compared to naked IL-12, most likely due to the rapid localization of collagen IL-12
to the tumor. This was in the absence of liver and kidney toxicity [65]. The strong regression of established tumors was attributed to the activation of innate (macrophage polarization, DCs) and adaptive immune cells (cytotoxic T lymphocyte responses) [65]. Also,
the combinational therapy with immune checkpoint inhibitors synergized tumorspecific antitumor immunity by highly expanding CD44
+
CD62LCD8+T cells and
tumor-infiltrating cytotoxic T lymphocytes [65].
Inhibiting antiinflammatory signaling enabled proinflammatory macrophage
polarization by upregulating proinflammatory signaling pathway. For example, the
M2-targeting liposome loading small interfering RNA (siRNA) CD115 inhibited the
expression of colony-stimulating factor 1 receptor (CSF-1R) which has been shown
to correlate with poor prognosis in cancer immunotherapy [66]. The M2-targeting
peptide-tethered liposomes encapsulating siRNA CD115 is capable of selectively
targeting M2 macrophages and delivering the payloads into the cells, down-regulating
the expression of CD115 to shift TAMs to M1 mode [66]. Suppressing CSF-1R by
liposome-based siRNA delivery diminished the population of CD206
and PD-L1
+
M2 TAMs and the secretion of IL-10 and TGF-β, but increased the pro-
duction of IL-12p70 and IFN-γ, thereby expanding the proportion of cytotoxic CD8
+
M2 TAMs
+
T cells (IFN-γ + CD8 + and CD69+CD8+T cells) alongside lowering the population of
tumor-suppressive T cells (TIM-3
+
CD8+and PD-1 + CD8+ T cells) [66].
Likewise, dual inhibition of CSF-1R and mitogen-activated protein kinase (MAPK)
pathways using NPs enhanced macrophage-based cancer immunotherapy [67]. Both
CSF-1R and MAPK pathways play a key role in activating antiinflammatory responses
to promote tumor growth, which is associated with a poor prognosis [67]. CSF-1R and
MAPK inhibitors, BLZ-945 and selumetinib, respectively, were tagged to cholesterol to
be incorporated into PEG-liposome-based NPs ( 100 nm) [67]. The dual inhibitor
delivery to M2 TAMs suppressed the phosphorylation of CSF-1R and extracellularsignal-regulated kinase, thus increasing M1/M2 ratios in the total macrophage population in vitro [67]. Moreover, the NP-mediated dual inhibitor delivery allowed TAMs to
upregulate the expression of CD80 and CD86 but downregulate that of CD206 by
inhibiting both CSF-1R and MAPK signaling pathways, highly generating proapoptotic
events in tumor tissues [67]. Inhibiting different signaling pathways also allowed for repolarization of macrophages to an M1 phenotype by activating proinflammatory
signaling [68].
The role of Janus kinases/signal transducer and activator of transcription (STAT) signaling pathway is to generate IL-4-mediated immune responses during M2 macrophage
polarization while inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ)isan
important upstream molecule regulating NF-κB [68]. In a recent study, the codelivery
of IKKβ siRNA and STAT-6 inhibitor-induced M2-to-M1 reeducation to boost the
efficacy of cancer immunotherapy with low immune adverse effects [68].
pH-responsive block-copolypeptide was designed not only to load both the molecules
but also to achieve M2-targeting delivery specifically to the tumor microenvironments
[68]. The dual inhibition of STAT-6 and IKKβ increased the expression of
M1-associated genes, IL-10, CD206, TGF-β, and Arg-1 but decreased that of
M1-associated genes, IL-12, CD80, TNF-α, and IFN-γ [68]. Moreover, NP-based
codelivery of STAT-6 inhibitor and IKKβ triggered M1 macrophage polarization and
then recruited cytotoxic CD4
+
and CD8+T cells into the tumor while repressing Treg
activity, thereby abrogating the progression of the tumor without immune adverse
effects [68].
The modulation of environmental factors across tumor microenvironments induced
proinflammatory macrophage polarization [69]. Hypoxia, oxygen-deficient conditions
around tumor tissues, is one of the prevalent characteristics of locally advanced solid
tumors [24,70]. TAMs that are responsive to hypoxia activate the constructive process
such as healing, tissue repair, and secretion of antiinflammatory cytokines [24,70]. Therefore, M2 TAMs activated by hypoxia boost the progression of the tumor by increasing
proliferation, angiogenesis, metastasis, and immunosuppressive signaling [70]. To quench
hypoxia, mannan-tagged hyaluronic acid-coated manganese oxide NPs specifically
targeted M2 TAMs and provide a large amount of oxygen throughout the tumor tissues,
thus reeducating M2 TAMs with inflammatory mode [69]. Manganese oxide NPs involved in chemical reactions between MnO
and H2O2produced a large amount of
2
219Challenges and opportunities of nanotechnology in cancer immunotherapy
220 DaeYong Lee et al.
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oxygen to attenuate tumor hypoxia [69]. The NP-mediated return to normoxia
upregulated iNOS and IL-12 expressions but reduced the expression of CD206 and
IL-10 [69].
The infliction of oxidative stress to TAMs is capable of resetting TAMs to M1 phenotype, which strengthens innate immunity against cancers [71]. In one study, photosensitizer and NH
HCO3-loaded mannose-tagged PEG-PLGA NPs skewed M2
4
macrophages to M1 phenotype by strongly exerting oxidative stress to M2 macrophages
[71]. When the NPs were internalized by mannose receptor-mediated endocytosis, the
NPs ruptured endolysosomes by producing CO
and NH3to release the photosensi-
2
tizer into the cytoplasm after laser irradiation, thereby generating ROS in surrounding
macrophages [71]. The laser triggered ROS overproduction achieved by the NPs
increased M1 makers, iNOS, IL-6, IL-12a, and CXCL10 but decreased M2 markers,
Arg-1, CCL22, Retnla, and IL-10, which was associated with activation of MAPK,
NF-κB, JAK/STAT signaling pathways [71]. The repolarization of TAMs by ROS
overproduction reinforced adaptive immunity by increasing the population of
+
IFN-γ
CD4+and IFN-γ+CD8+T cells, which result in the dramatic inhibition of
tumor growth and also increase in survival [71]. As another example, iro n oxide
NPs can stimulate the reeducation of M2 macrophages, which was attributed to Fenton
reactions-mediated ROS production (Fig. 4) [72,73]. Food and drug administrationapproved iron supplement ferumoxytol, a dextran-coated iron oxide NP, rendered
M2 macroph age to p roinflammatory mode to elicit antitumor immunity [72].The
uptake of ferumoxytol in macrophages elevated intracellular ROS levels in that the
increase in cytosolic iron level actively catalyzed the Fenton reaction, which consequently upregulated M1 markers, iNOS, TNF-α, and CD86 but decr eased the expression of M2 markers, Arg-1, CD206, and IL-10 [72]. The reeducated macrophages
inhibited tumor progression and also prevented liver and lung metastases whereby
the po pulation of proinflammatory macrophages was higher [72]. In a mechanistic
study, iron oxide NPs were syn thesized by coating Fe
on silica NPs, in which ferric
3O4
and ferrous ions are released at lysosomal pH [73]. The iron overload in macrophages
elevated intracellular ROS concentrat ion resulting in the increased expression level of
CD80, CD86, CD64, and IL-23 along with reduction of CD206 and Arg-1 [73].
Reprogramming macrophages via iron overload mainly relied on activation of irondependent interferon regulatory factor (IRF) 5-IL-23 signaling pathway rather than
ROS-induced NF-κB-iNOS pathway [73].Thein vivo study using a tumor-bearing
mouse model demonstrated that iron oxide NPs retarded tumor proliferation, which
was attributed to iron overload-activated macrophage polarization [73].
Macrophage polarization has also been observed with the hybrid of β-alanine and
gadofullerene and resulted in reinvigorating both innate and adaptive immunity [74].
The functional gadofullerene NPs increased M1-associated markers, TNF-α, IL-6,
IL-12, IL-23, and iNOS, but decreased M2-associated markers, IL-10, Arg-1, and
CD206, which resulted from the activation of NF-κB, AP-1, and IRF-5 signaling
221Challenges and opportunities of nanotechnology in cancer immunotherapy
pathways [74]. Combinational therapy with PD-1 antibody remarkably suppressed the
established tumor by recruiting cytotoxic CD4
+
and CD8+T cells into the tumor, which
was attributed to proinflammatory macrophage polarization [74].
NPs extracted from cuttlefish ink can not only implement NIR laser-triggered PTT
but also polarize macrophages to M1 mode for synergistic cancer therapy [75]. Cuttlefish
ink composed of melanin, polysaccharides, oligopeptides, and metals. is endowed with
inherent biological properties, which can be harnessed for biomedical applications [75].
The treatment of cuttlefish ink NPs promoted the expression of CD86, TNF-α, iNOS,
IL-12p40 alongside lowering that of Arg-1 and CD206, thus reprogramming M2 to M1
[75]. The macrophage polarization achieved by cuttlefish ink NPs was mainly dependent
on MAPK and NF-κB signaling pathways [75]. The combined therapy with PTT amplified the expression of CD80 and CD86 on TAMs and also secretion of IL-6, IL-12p40,
TNF-α, and IFN-γ, which resulted in the recruitment of cytotoxic CD4
+
and CD8
T cells into the tumor [75].
4.2 Phagocytosis activation
Reinforcement of innate immunity is indispensable for activating adaptive immunity by
cross-presentation of APCs, leading to recruitment of antigen-specific T cell responses
[76]. APCs require the engulfment of tumor cells through phagocytosis which requires
coordination of several cellular processes, such as tumor recognition, engulfment, and
lysosomal digestion [76]. In general, tumor cells block phagocytosis from APCs by overexpressing antiphagocytosis proteins on the cell surface, which brings about the failure of
cancer immunotherapy [76]. Inducing phagocytosis-promoting signals in cancers allows
APCs to awaken the phagocytosis ability, which can overcome the limited therapeutic
effectiveness of immunooncology [76]. Several prophagocytosis proteins, CRT, signal-
ing lymphocytic activation molecule family member seven and Fc receptors enable APCs
to improve immune surveillance against tumor and promote phagocytosis, strengthening
innate immunity [76].
To harness prophagocytosis markers with nanotechnology, NPs have been designed
incorporating CRT proteins and cancer cell targeting antibodies. In turn, they can target
cancer cells and activate phagocytosis of specific cancer cells by recruited macrophages
without stimulating inflammatory signaling pathways (Fig. 5) [77]. In one study,
CRT proteins and HER (human epidermal growth factor receptor (HER) two antibodies were conjugated on the surface of carboxylated polystyrene NPs, used as a core
scaffold to synthesize multivalent nanobioconjugate (Fig. 5) [77]. The multivalent nanobioconjugate first targeted HER2-positive breast cancer cells and then recruited macrophages to increase phagocytotic activity (Fig. 5) [77]. Selective induction phagocytosis
against HER2-positive breast cancer cells enhanced CD4
and also increased the population of CD44
+
CD62LCD4+and CD8+T cells playing a
crucial role in a specific killing [77]. The multivalent nanobioconjugate inhibited tumor
+
and CD8+T cell activation
+
222 DaeYong Lee et al.
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Fig. 5 Phagocytosis-activating NPs enhanced the capability to recognize and phagocytosize cancer
cells, thus activating APCs and their downstream to induce specific killing.
growth specifically in HER2-positive tumors by recruiting effector CD4+and CD8
T cells, and also showed systemic and durable antitumor immunity as tumor recurrence
was completely abolished even after rechallenging of tumor cells [77].
Deactivation of antiphagocytic signals increased the capability to recognize and
phagocytosize tumor cells [76]. “Don’t eat me” signal-activating is capable of evading
immune recognition and abolishing phagocytosis by APCs [76]. To disturb the
receptor-ligand interactions between tumor cells and APCs, several phagocytosis checkpoints have been discovered that exhibit enhancement of phagocytic activity by minimizing antiphagocytic signaling [76]. CD47-signal-regulatory protein α (SIRPα) axis
is a promising target to activate the phagocytosis of cancer cells because immune evasion
of cancer cells is abolished, thus enhancing antitumor immunity [76]. The delivery of
CD47 antibody combined with nanotechnology is capable of de-activating ‘Don’t eat
me’ signals to maximize the phagocytosis of tumor cells by APCs [78]. For one example,
ROS-responsive NPs incorporating PD-1 and CD47 antibodies achieved controlled
release of PD-1 and CD47 antibodies in tumor microenvironments, thereby reinforcing
both innate and adaptive immunity [78]. The ROS-sensitive NPs were designed by
+
cross-linking three components, PD-1 antibody, CD47 antibody, and albumin with
thioketal linkers [78]. CD47 antibody on the NPs was able to selectively target tumor
cells overexpressing CD47 on their surface, and the ROS-enriched tumor microenvironment rapidly deconstructed the ROS-responsive NPs, thereby releasing the payloads
across the tumor tissues [78]. The ROS-triggered release of both the antibodies expanded
the population of CD80
that of CD206
+
macrophages and Tregs, which was attributed to a decrease in ROS level
+
CD86+macrophages and cytotoxic CD8+T cells but reduced
across tumor microenvironments de-activating NF-κB and MMP2 signaling pathways
[78]. Strengthening both innate and adaptive immune responses by the ROS-responsive
NPs suppressed both the primary and metastatic tumors by establishing robust and systemic antitumor immunity [78]. Additionally, the blockade of the CD47 receptors on
cancer cells utilizing SIRPα-containing exosomes also elevated the phagocytic activity
to enhance antitumor immunity (Fig. 6) [79]. The SIRPα-expressing exosomes were
prepared by transfecting HEK293 cells with plasmid DNA encoding SIRPα followed
by ultracentrifugation-based isolation [79]. The SIRPα exosomes selectively bound to
CD47 receptors overexpressed on cancer cells, which activate phagocytosis of the cancer
cells (Fig. 6) [79]. The enhanced phagocytosis by SIRPα exosomes-mediated CD47
blockade resulted in retarded tumor growth compared with the monomer of SIRPα
in vivo (Fig. 6) [79]. In an advanced study, CD47-binding nanocages with doxorubicin
inducedphagocytosis of tumor cells and also prompted immunogenic cell death for synergistic therapeutic effect [80]. The therapeutic nanocage was designed by surfaceengineering human ferritin with SIRPα protein to specifically bind and antagonize
CD47 [80]. The SIRPα-tethering nanocage highly interacted with CD47 receptors
on cancer cells, which was associated with a higher binding affinity of the SIRPαtethering nanocage than a SIRPα monomer [80]. The CD47 blockade using the
SIRPα-tethering nanocage boosted phagocytosis of cancer cells overexpressing CD47
receptors compared to the SIRPα monomer, thus possessing an antitumor effect [80].
223Challenges and opportunities of nanotechnology in cancer immunotherapy
Fig. 6 T cell-activating NPs activate naïve T cells by inhibiting immunosuppressive signals or activating
immunstimulatory molecules, thus sensitizing cytotoxic T cell immunity to induce specific killing.
224 DaeYong Lee et al.
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Furthermore, the SIRPα-tethering nanocage with DOX significantly abrogated tumor
growth, resulting from priming effector CD8
+
T cells and secreting IFN-γ [80].
Inhibiting signaling pathways related to the CD47-SIRPα axis not only reeducated
macrophages with proinflammatory mode but also promoted engulfment of tumor cells
by macrophages [81]. CD47, a transmembrane protein overexpressed on cancer cells,
activates Src homology region 2 domain phosphatases, SHP-1 and SHP-2 in macrophages, thus activating “Don’t eat me” signaling pathway [81]. To promote macrophage
polarization and also phagocytosis, both the inhibitors, SHP-2 and CSF-1R, were loaded
into PEG-liposomes [81]. The treatment of dual inhibitors using the liposome NPs
allowed for promoting phagocytosis of cancer cells by inhibiting SHP-2 as well as reprogramming macrophages with M1 mode by inhibiting CSF-1R signaling [81]. When the
liposome NPs were applied in vivo, the tumor growth was repressed by increasing M1/
M2 ratio and priming cytotoxic CD4
+
and CD8+T cells, which was attributed to dual
inhibition of CSF-1R and SHP-2 [81].
4.3 NK cell activation with nanotechnology
NK cells are a type of lymphocyte possessing both innate and adaptive immune characteristics and that have been shown can eliminate cancer cells [82]. NK cells can recognize
and kill tumor cells without prior sensitization, which is reliant upon costimulatory and
inhibitory receptors. Besides NK effector functions, they are also able to trigger the production of cytokines and chemokines, which awakens both innate and adaptive immune
responses [83,84]. In general, tumor microenvironments abate immune-stimulating factors by upregulating immune checkpoints and antiinflammatory signaling, thus suppressing the activity of NK effector functions [83,84]. In order to sensitize the function
of NK cells, the blockade of immune checkpoints restores the NK cell activity, consequently enabling the recruitment of immune cells into the tumor and specific killing
[83,84]. In addition, genetic modification of NK cells (e.g., CAR NK cell therapy)
unprecedentedly maximized the capability to induce specific killing [83,84]. To improve
the potency of NK cell-based therapy, utilizing nanotechnology-enabled the sensitization of NK cell activity but also augmentation as efficient cancer immunotherapy. In this
section, we discuss how nanotechnology is used in NK cell-based therapy and how the
NPs enhanced the potency of NK cell-based immunotherapy.
Combining NK cell-stimulating antibodies with nanotechnology is a straightforward
approach to activate NK cells, enabling the implementation of efficient cancer immunotherapy [85]. In one study, trispecific NK cell nanoengagers were able to elicit enhanced
antitumor immunity, providing robust chemoimmunotherapy. PEG-PLGA NPs loading
epirubicin was loaded with EGFR, CD16, and 4-1BB antibodies to simultaneously target
EGFR-positive cancer cells and stimulate NK cells [85]. Trispecific nanoengagers
targeted EGFR
+
cancer cells and then activated the recruited NK cells to attack cancer
cells, which showed a higher antitumor effect compared to the mono-treatment of antibodies [85]. The in vivo study showed that the trispecific nanoengager suppressed tumor
growth in EGFR-overexpressing tumor but not in EGFR-negative tumor, indicating
that the trispecific nanoengager was able to selectively recruit and activate NK cells into
EGFR tumor only for specific killing [85].
NK cells combined with drug-loaded NPs allowed for selective cancer targeting via
immune recognition and augmentation of antitumor therapeutic efficacy by exploiting
the formation of NK cell-tumor cell immunology synapse [86]. Maleimide PEG-poly(-
β-aminoester) was synthesized to not only load DOX but also adhere the NPs on the
surface of NK cells using thiol-maleimide conjugation chemistry [86]. The NK cells
embedded with DOX-loaded NPs attack tumor cells, and then the NPs rapidly released
the payloads to tumor cells by immune synapse acidification, resulting in a synergistic
antitumor effect [86]. Its hybrid approach remarkably abrogated tumor progression compared to NK cell treatment and DOX-loaded NP treatment, which efficiently
implemented chemoimmunotherapy [86].
Engineering NK cells with multifunctional NPs allows for bioimaging function as
well as induce specific-killing to the tumor. Magnetic NPs were coated with polyethylene imine condensing plasmid DNA encoding EGFR-CAR to engineer NK cells [87].
The treatment of multifunctional NPs allowed the NK cells to express EGFR CAR on
the cell surface without altering the expression of activation and repression receptors on
NK cells [87]. The administration of EGFR CAR-expressing NK cells highly inhibited
tumor proliferation in EGFR-positive cancer models compared to nonengineering of
NK cells with EGFR CAR [87]. Moreover, the magnetic NPs trapped into NK cells
facilitated the tracking of the NK cells around tumor tissue via magnetic resonance [87].
225Challenges and opportunities of nanotechnology in cancer immunotherapy
5. T cell activation
T cells play a crucial role in cell-mediated adaptive immunity to specifically kill
tumor cells [1]. In cancer immunotherapy, naı¨ve T cells should be primed to be activated
to effector T cells by professional APCs presenting MHC-II, antigens, and immunostimulatory markers [1]. Consequently, effector CD8
interact with the tumor cells by recognizing the corresponding antigen expressed on their
cell surface, and eventually induce antigen-specific cell death [1]. Given T cells are found
throughout the tumor microenvironment, several immunosuppressive signals are activated by immune checkpoints or tumor cells releasing antiinflammatory cytokines
(e.g., TGF-β), which negatively influences effector T cell function [88,89]. To restore
the effector T cell functions, the blockade of immune checkpoints or CAR-T cell therapy has been developed and shown the exceptional therapeutic index in clinical trials
[2,3]. Unfortunately, only a small portion of patients have beneficial results and also those
+
T cells infiltrate into the tumor,
226 DaeYong Lee et al.
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therapeutic approaches are not usually effective in solid tumors [3]. The combination of
the strategies with nanotechnology can overcome the hurdle of unsatisfactory therapeutic
index and broad applicability to various tumor models. We elucidate how nanotechnology improves the therapeutic efficacy in cancer immunotherapy.
5.1 Activating T cell immunity with nanotechnology
T cells were exhausted by several environmental factors; immune checkpoints,
PD-1-PD-L1 axis and CTLA-4, antiinflammatory cytokines, and ionic checkpoint
[88–90]. The treatment of several inhibitors rendered T cell immunity restored by
reactivating immune recognition against cancer [88–90]. To achieve enhanced therapeutic efficacy without side effects, nanotechnology has been utilized both as a delivery vehicle but also as a self-stimulator. We will discuss several NP strategies delivering reagents to
strengthen T cell immunity or stimulating its function by itself.
TGF-β is a major mediator of immune suppression, which is one of the major reasons
for deactivating T cell immunity [91]. However, the systemic administration of TGF-β
inhibitors brings about undesired cytotoxicity and low effectiveness of cancer immunotherapy [91]. To address the critical problem, T cell targeting NPs with TGF-β inhibitors
were designed by using PEG-PLGA NP as a core material followed by attaching T cell
targeting antibody (CD8a or PD-1) [91]. CD8a-targeting NPs and PD-1 targeting were
taken up by CD8a
targeting delivery of TGF-β inhibitors to T cells significantly expanded the population of
effector T cells and also activate the secretion of granzyme B and IFN-γ into tumor tissues, thereby suppressing tumor proliferation [91]. Besides, The PD-1 targeting delivery
of R848, TLR-7/8 agonist, showed synergistic antitumor immunity by reinforcing both
innate and adaptive immunity to eradicate the tumor [91].
MHC-I along with costimulatory markers in APCs are necessary to activate the cognate T cells that can target and kill tumor cells expressing the corresponding antigen [92].
Using this principle, NPs incorporating CD80 and MHC-I peptide were designed by the
transfected cancer cell lysate to stimulate naı¨ve T cells [92]. Wild-type cancer cells were
transfected with CD80-encoding plasmid DNA to express CD80 on the cell surface and
then lysed to form antigen-presenting NPs. The antigen-presenting NPs directly interacted with T cell receptors and CD28, thus leading to stimulation of T cells for specific
killing [92]. The antigen-presenting NPs increased the proportion of both memory
+
(CD44
CD62L+) and effector (CD44+CD62L) CD8 + T cells and also increased
IL-2 and IFN-γ [92]. Furthermore, the expression of CD69, a hallmark of T cell activation was significantly augmented [92]. The activation of T cell immunity achieved
by the antigen-presenting NPs abrogated the progression of tumors and also extended
the survival by generating systemic and robust T cell-based antitumor immunity [92].
In a different study, NPs tethered with MHC-I and CD28 antibody on their surface acted
+
T cells and PD-1+T cells in vivo, respectively [91]. The NP-mediated
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