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Reviews: Part IV: Novel Therapeutic Strategies for Cancer

Nanomedicines Targeting the Tumor Microenvironment

Tong, Rong PhD*†; Langer, Robert ScD*

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doi: 10.1097/PPO.0000000000000123
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Cancer nanomedicine refers to the application of nanotechnology-based therapeutics and imaging agents for the diagnosis, monitoring, prevention, and treatment of cancer.1 Cancer nanomedicine is expected to change the oncology by delivering a wide range of payloads with favorable pharmacokinetics, capitalizing on molecular targeting for enhanced specificity, efficacy, and therefore safety. Tumor vasculature is typically permissive for transvascular transport of nanomaterial sizes less than 100 μm, and lymphatic dysfunction in tumor causes poor clearance of nanomaterials—both allow for enhanced permeation and retention (EPR) of NPs into tumor.2 The hyperpermeability of tumor vessels3 and dysfunctional tumor lymphatic vessels4 has been observed in human patients’ tumors, suggesting the existence of the EPR effect in human tumors. The EPR effect has been demonstrated to be the key pharmacokinetic feature for passive tumor targeting and reduced systemic toxicity with cancer nanomedicines.5

Many nanomaterials have been used as drug delivery vehicles and/or imaging agents. They include liposomes; polymer carriers, such as micelles, hydrogels, polymersomes, dendrimers, and nanofibers; metallic nanoparticles (NPs) (gold, silver, etc.); carbon nanostructures (nanotubes, graphene, etc.); inorganic NP, such as silica NP; and hybrid nanomaterials.6 Different classes of nanomaterials with unique properties are optimal for specific applications. For example, the incorporation of chemotherapeutic agents in liposomal or polymeric NP delivery vehicles has exhibited improved drug solubility, reduced drug clearance, reduced drug resistance, and enhanced therapeutic effectiveness.7,8 Several NP therapeutics, for example, Doxil (∼100-nm PEGylated liposome loaded with doxorubicin) and Abraxane (∼130-nm albumin-bound paclitaxel NPs), have been approved by the US Food and Drug Administration and have shown improved pharmacokinetics and reduced adverse effects compared with their parent drugs.9,10 In addition, metallic particles are promising therapeutic agents that convert light to heat (photothermal effect) to kill cancer cells, with clinical trials in head and neck cancer and lung cancers.11 Small inorganic NPs, for example, silica NPs, are in clinical trials as positron emission tomography–optical imaging agents for lesion detection and cancer staging.12

Although nanomedicine has made tremendous progress, it is still questionable whether the EPR effect is sufficient to significantly improve the survival of patients with cancer by nanomedicine.13 Indeed, the abnormal tumor microenvironment contains several delivery barriers to limit the transport of NPs deep into tumors (Fig. 1).5 The distribution of NPs from the bloodstream into tumors is impeded by tumor blood flow stasis or collapsed tumor blood vessels.3 The excessive vessel leakiness and blood flow stasis also bring out high interstitial fluid pressure that considerably hinders the extravasation of NPs.14 The NP access deep into tumors is often hindered by the large distance between blood vessels in tumors15,16 and by the dense interstitial matrix, a complex assembly of collagen, glycosaminoglycans, and proteoglycans.17 For example, Doxil and Abraxane are found trapped less than 100 μm away from vessels.18,19 Recent advance in biology also shows that many factors in the tumor microenvironment contribute to the tumor escape from immune system surveillance, including the expression of T cell–inhibitory molecules,20 the activation of T cells resulting in anergy,21 and the presence of both CD4+CD25+ T cells and CD1d-restricted T cells that suppress antitumor immunity.22,23 Such abnormal tumor microenvironments help tumor progress and resist the treatment. Therefore, the nanomedicine has to be designed to overcome the delivery barriers in tumor microenvironment to improve the therapeutic efficacy.24

Strategies to overcome the delivery barriers in tumor microenvironment. The abnormal tumor vasculature, dense collagen matrix, elevated interstitial fluid pressure, and collapsed vessels in the tumor interior present barriers to NP penetration deep into tumors. The abnormal tumor microenvironment has to be normalized to increase the NP accumulation and penetration in tumor.

In this review, we discuss the advance to use nanomedicine to overcome delivery barriers, especially such in the tumor microenvironment. We first discuss recent studies on the physicochemical properties of nanomedicine to develop NP-tumor interaction and to enhance the delivery in tumors (Physicochemical Properties of Nanomedicine). We feature the advances in stimulus-responsive delivery that can drive NP accumulation and penetration in tumor (Stimulus-Responsive Drug Delivery). We highlight some emerging strategies to manipulate tumor microenvironment by nanomedicine, through normalization approaches (Nanomedicine Targeting the Tumor Microenvironment). Nanomaterials for cancer immunotherapy that can change the immunosuppressive tumor microenvironment will also be reviewed (Nanomedicines for Cancer Immunotherapy).


To achieve therapeutic efficacy, NPs must first overcome systemic barriers with prolonged circulation time, especially clearance by mononuclear phagocytic system, hepatobiliary system, and urinary system.25 Then NPs extravasate from tumor vessels and penetrate the tumor parenchyma so that even cancer cells situated distal to the tumor vessel can be exposed to the anticancer agent at high-enough concentrations. These nanomedicine delivery processes are largely affected by physicochemical properties of NPs, including size, surface charge and chemistry, and geometry.

Nanoparticle Size

Nanoparticles with sub–100-nm sizes appear to be optimal for the EPR effect.26,27 However, NPs must penetrate up to hundreds of micrometers through stroma to reach cancer cells. Therefore, deep penetration of NPs in tumors is necessary for therapeutic effect.28 Nanoparticle size is a crucial determinant of accumulation and penetration into tumor tissue. Small NPs usually have deeper tumor penetration than large NPs, but there remains discrepancy of intratumoral accumulation trend of different-sized sub–100-nm NPs in many references.26,29–31 It is reported that polymeric micelles ∼30 nm showed enhanced tissue penetration and potent antitumor activity in pancreatic tumors, compared with larger NPs.31 In another example, 50-nm silica NPs showed deep tissue penetration and higher accumulation in breast tumors over time, compared with 20-nm or larger NPs.26,30 Of note, recent studies showed that ∼15-nm gold NPs surface-decorated with siRNA could pass through a compromised blood-brain barrier and accumulate in glioblastoma.32

Nanoparticle Surface Chemistry

In addition to size, the surface chemistry of NP, especially surface charge, affects their tumor penetration. It is reported that cationic NPs extravasate more rapidly in tumors than neutral or anionic particles because of the attractive electrostatic forces between cationic NPs and anionic endothelial glycocalyx.33–37 However, neutral NPs display the fastest interstitial transport than charged NPs presumably because of the minimized NPs binding to anionic glycosaminoglycans or positively charged collagens.38–40

Besides tumor penetration, the surface chemistry of NP is well known to influence the NP circulation and biodistribution. Nanoparticles often have prolonged circulation in the blood compared with small-molecule drugs (<5 nm).7,41 Macrophages in the reticuloendothelial system can engulf and clear injected NPs, which can lower the dose of NPs reaching tumors. Moreover, the macrophage uptake of NPs can lead to compromised host defenses (due to the saturation of macrophage uptake capability by NPs),42 release of toxic byproducts (from exposing NPs to highly oxidative environment upon phagocytosis),43 and redistribution of NPs to the liver and spleen that potentially can induce delayed or chronic toxicity.44–46 Coating of NPs with poly(ethylene glycol) (PEG) that mimics a cell’s glococalyx,47–49 known as “PEGylation,” can suppress protein absorption to NPs and delay the rate of NP uptake and clearance, greatly prolonging circulation time. However, PEGylation cannot eliminate macrophage uptake that is not mediated by serum absorption.50

An intriguing approach to evading phagocytosis of NPs was to graft a synthetic small peptide, which was computationally designed from CD47, a cell surface “marker of self” that impedes macrophage uptake,51 to mimic the CD47-CD172a interaction that inhibits phagocytosis. This peptide prolonged the circulation time of NPs in vivo.52

Nanoparticle Geometry

The aspect ratio of nanomaterials affects their interaction with cells (e.g., uptake),53 in vivo circulation time, and tumor penetration capability.54,55 For example, flexible polymeric cylindrical micelles had much longer circulation times in vivo than their spherical counterparts.56 Interestingly, rigid carbon nanotubes with lengths of 100 to 500 nm and diameters of 1 nm (aspect ratio ∼100–500) can be rapidly renally cleared (circulation half time ∼6 minutes).57 In addition, it is reported that nonspherical gold NPs, for example, nanorods and nanocages, could penetrate tumors more thoroughly than the similar-sized nanospheres and nanodisks; however, higher intratumoral accumulations were observed for gold nanorods and nanospheres than their nonspherical counterparts.58


To enhance the preferential accumulation of NPs or drug release in tumors, there have been increasing efforts to develop stimulus-responsive nanomaterials that utilize endogenous or exogenous stimuli to overcome the limitation of EPR.59,60 Local tumor microenvironmental factors, such as pH (6.7–7.0),61 redox state (hypoxic tumor microenvironment62 and elevated reactive oxygen species generated by tumor cells63), and specific molecules overexpressed in tumor (e.g., matrix metalloproteinases),64 can disrupt NP structure to release loaded drugs; however, only a few utilize endogenous stimuli (e.g., matrix metalloproteinase 2) to enhance NPs’ tumor penetration.28 Exogenous stimuli include electromagnetism, heat, ultrasound wave, and light. Such spatiotemporal control over the activation of materials may drive localization, maximize cargo release at the desired tumor site, improve NPs’ tumor penetration, or change the tumor microenvironment.65,66 Some means of activation such as ultrasonic waves, sophisticated light sources, or strong magnetic fields may not always be practical or cost-effective. Another problem related to the application of exogenous stimuli is the depth of tissue penetration that can be expected, which has been discussed elsewhere.67,68

A major challenge with many stimulus-responsive delivery approaches is to translate relatively complicated designs from the bench to a successful in vivo application. Many triggerable systems have been reviewed elsewhere59,60,65,66; here we will highlight the progress in this area.

Photothermal Therapy

Local heating of tumors to ∼41°C to 43°C, known as hyperthermia therapy, has been shown to increase the blood flow to and permeability of tumor vessels.69 Liposomes have been designed to release drugs when tumors are preheated,70 and such thermosensitive liposomes containing doxorubicin are currently in clinical trials.71 However, the conventional hyperthermia often takes ∼30 to 60 minutes to heat tumors. More rapid heating (within minutes)11 can be achieved by irradiating metallic NPs that have surface plasmon resonance (e.g., gold NPs and CuS NPs), which efficiently absorb light and convert it to heat.72,73 The photothermal properties of gold NPs have been utilized to enhance the accumulation of subsequently administered conventional NPs in tumors (Fig. 2A).74,75

Light-triggered drug delivery. A, Photothermal therapy that converts light to heat can enhance the tumor permeation. B, Photoswitchable NPs (100 nm, orange spheres) can shrink to 40 nm (purple spheres) upon light illumination. The smaller NPs will have enhanced tissue penetration. Release of drugs (bright yellow spheres) loaded in the NPs is simultaneously triggered by light.

Organic NPs can be also used to enhance the drug delivery utilizing photothermal sensitizer molecules. Nanoliposomes composed of lipid conjugates of the photosensitizer pyropheophorbide (a chlorin analog) can efficiently absorb and transfer light energy into heat for photothermal therapy. The same nanoliposome can also carry doxorubicin for chemotherapy. Irradiation of the nanoliposomes in tumor induces photothermal effects, and the generated heat enhances tumor permeation, which allows for enhanced doxorubicin accumulation over 24 hours.76,77

In addition to enhance tumor vessel permeability, NPs with photothermal properties can induce tumor microenvironment change to “recruit” a second group of therapeutics into tumors. In 1 application, the photothermal properties of gold NPs disrupted tumor vessels; the resulting local overexpression of fibrin was used as a target for the accumulation of a second group of NPs surface-modified with a peptide targeting fibrin administered 72 hours later.74

The type of NPs used in photothermal therapy can be also used as the heat source for thermoresponsive drug delivery systems. For instance, thermoresponsive polymers coated on hollow porous gold nanostructures78 shrink upon irradiation, uncovering the pores and allowing drug efflux. The use of light to trigger drug release from such type of NPs has been reviewed elsewhere.65

The combination of NPs for photothermal therapy with photoacoustic tomography imaging techniques may provide a strategy for simultaneous diagnosis and treatment of cancers,73 because both techniques utilize near-infrared (NIR) light. Photoacoustic imaging is an ultrasonic imaging technique in which wide-band ultrasonic waves can be induced by a pulsatile excitation laser (NIR laser) due to thermoelastic expansion of tissues. The loss of signal in photoacoustic imaging is negligible compared with other optical imaging techniques, because acoustic waves have 2 to 3 orders of magnitude less scattering in tissue than light.79 Inorganic NPs absorbing NIR light (e.g., gold NPs80–84) have recently been shown to be improved contrast agents for photoacoustic imaging, which can be also used for photothermal therapy. For example, accurate and efficient ablation of tumor by photothermal therapy has been achieved by simply switching laser power from a power suitable for photoacoustic imaging (50 mW/cm2) to one suitable for photothermal therapy (16 W/cm2, 3 minutes) with the administration of hollow gold NPs.82

Nanomaterials for Light-Triggered Drug Delivery

Light-triggered nanomaterials have also been used for enhanced tumor penetration with the tuning of both NP size and tumor vasculature. We recently developed a photoswitchable spiropyran-based drug delivery NP with a light-induced reversible volume change from 100 to 40 nm (Fig. 2B).85 The volume change of the monodisperse NPs enabled repeated drug release and enhanced NP diffusion into tumors. Triggered release of docetaxel from the NPs decompressed tumor vessels by inducing tumor cell apoptosis and prompted NP penetration into and accumulation in the tumor interior.86


Antiangiogenic Therapy for Vasculature Normalization

Antiangiogenic therapy can “normalize” the tumor vasculature by inducing vessel maturation such that there is increased perfusion and more evenly distributed vasculature within tumors.87 This normalization has been suggested as a means of modulating of tumor microenvironment and perhaps improving NP delivery into tumors (Fig. 1). Recently, it was found that blocking vascular endothelial growth factor receptor 2 in mouse mammary tumors greatly improved the delivery of small NPs (12 nm) but not larger NPs (such as 60 and 125 nm).29 The explanation for this observation may be that the normalization of the tumor vasculature by anti–vascular endothelial growth factor receptor 2 agent decreased the tumor vessel wall pore size, which then only allowed the smaller NPs (<60 nm) to be rapidly transported in tumor tissue.

Targeting Tumor Extracellular Matrix

In solid tumors, penetration of macromolecular agents and NPs is affected by tumor stromal barriers such as the extracellular matrix (ECM, e.g., collagen network, and hyaluronic acid).17 Numerous studies have shown that ECM-degrading enzymes, such as collagenase or hyaluronidase, can improve NP penetration into solid tumors (Fig. 1).88–90 However ECM-degrading agents may increase the incidence of metastasis.91 The antihypertensive drug, for example, losartan, was recently found to reduce tumor collagen content by blocking angiotensin II receptor 1 and has been successfully used to enhance diffusive transport and efficacy of intravenously administered NPs such as Doxil.92,93 However, in a recent multicenter phase II clinical study, combined chemotherapy with gemcitabine and candesartan, a losartan analog, failed to demonstrate prolonged progression-free survival in patients with advanced pancreatic cancer.94 A safety concern was also raised because hypotension induced by candesartan was observed in some patients. In addition, PEGylated form of recombinant human hyaluronidase (PEGPH20) has recently been introduced into clinical trials (trial IDs NCT00834704, NCT01170897, NCT01959139) with the combination of Abraxane or other chemotherapeutics. It is reported that high doses of PEGPH20 (50 μg/kg) induced severe (grade 3) muscle/joint pain, whereas low doses were generally well tolerated.95

Tumor-Penetrating Peptides for Enhanced Tumor Penetration

Tumor-penetrating peptides, such as iRGD (a cyclic RGD peptide, CRGDKGPDC) and Lyp-1 (CGNKRTRGC), were identified by phage library screening and were able to enhance drug or NP penetration into tumors.96,97 The iRGD peptide is proteolytically degraded into its active form and bound to neurophilin 1, which is expressed in tumor vasculature and tumor cells, and induces endocytic bulk transport through tumor tissue; the detailed pathway for tissue penetration and endocytosis is still being elucidated.98 Coadministration of such peptides with Abraxane NPs or Doxil liposomes significantly increased their intratumoral accumulation.96

Targeting Tumors Utilizing Tumor Metabolism

It is known now that tumor cells are highly metabolically active and favor the inefficient anaerobic glycolysis (uptaking glucose).99 The 18F-labeled fluoro-2-deoxyglucose, a glucose analog, has been widely used in oncology for tumor diagnosis (by positron emission tomography) and staging.100,101 Recently, such saccharide metabolism has been utilized to introduce the chemical functional group on the cell surface. For example, aminosugars containing 1 unnatural functional group (e.g., azide) can be taken up by cells and expressed on their surfaces; the introduced functional group can undergo bioorthogonal chemistry to artificially label the cells.102 Bioorthogonal chemistry refers to a variety of chemical reactions using functional groups that generally do not occur in the host creature and that do not interfere with native biochemical reactions.103 Such bioorthogonal reactions include azide-alkyne cycloaddition, azide-phosphine Staudinger ligation, and tetrazine-cyclooctene Diels-Alder reactions.104,105 A 2-step in vivo tumor-targeting strategy has been developed to enhance intratumoral NP accumulation (Fig. 3).106 The first step involved treating the tumor with an unnatural glycan containing an azide group, via intratumoral injection. Cancer cells would take up the glycan and express it, with its azide groups, on the cell surface. When NPs containing alkyne groups were administered systemically, they underwent a bioorthogonal reaction with the azides in the tumor, leading to enhanced intratumoral accumulation of NPs. Bioorthogonal tumor-targeting strategies can also be applied to tumor imaging. Tumor cells prelabeled with antibodies modified with cyclooctene were implanted subcutaneously, and perfluorocarbon microbubbles surface-modified with tetrazine groups were injected systemically and reacted with cyclooctene on the tumor cells, which could now be better imaged by ultrasound in vivo.107 Bioorthogonal approaches are intriguing, but the initial step of introducing the unnatural functional group into tumors is often technically challenging.

Schematic illustration of tumor targeting using bioorthogonal reactions. Tumor cells are first fed with unnatural aminosugars containing 1 functional group for the bioorthogonal reaction. That functional group is later expressed on the tumor cell surface and can react via a bioorthogonal reaction with NPs (green sphere) surface-modified with another functional group.


Tumor once thought as simply the growth of malignant cells has been proved to be fueled by localized immunosuppression.108 The idea of a therapeutic cancer vaccine originated with the discovery that patients can harbor CD8+ and CD4+ T cells specific for cancer-testis antigens expressed in their tumors.109 In addition, clinical studies showed a strong association between prolonged patient survival and the presence of intratumoral CD3+ or CD8+ cytotoxic T cells with an interferon γ gene signature.110,111 The understanding of the molecular basis of immune activation, especially the research on T-cell receptors subunits and T-cell receptor costimulatory and coinhibitory molecules,112,113 paves the path to current promising cancer immunotherapy with recent success of proof-of-concept clinical trials.114 One prominent example of activating the immune system against tumor is the anti–CTLA-4 antibody, ipilimumab, which prevents CTLA-4 from attenuating T-cell activation. The use of ipilimumab achieves a significant increase in survival for patients with metastatic melanoma, which cannot be effectively treated by conventional therapy.115 In addition, lambrolizumab and nivolumab, 2 antibodies that target the programmed cell death 1 receptor on activated T cells, remove the brakes imposed by coinhibitory molecules so that cancers can be recognized and destroyed by the immune system.116,117

The use of nanomaterials in cancer immunotherapy can deliver agents to specific organs (e.g., lymph nodes [LNs]) or cells. In particular, NPs have been utilized to target immune cells inside LNs or mucosal tissues to induce immune responses toward tumors. Nanoparticle size directly affects which immune cells the NPs enter.118 Upon systemic administration, particles between 500 and 2000 nm are generally processed by antigen-presenting cells (APCs) at the injection site, whereas sub–200-nm NPs can traffic to the LNs where they are captured by LN-resident dendritic cells (DCs).119 In another example, after intradermal injection, 25-nm NPs can flow through lymphatic capillaries to the draining LNs, whereas 100-nm NPs cannot be transported to LNs.118 Such size-dependent LN targeting has been utilized for both imaging and vaccination. In 1 example, 16-nm iron oxide/zinc oxide NPs carrying carcinoembryonic antigen were injected into the mouse footpad and trafficked to draining LNs. The NPs could be imaged by magnetic resonance imaging, because of the iron oxide, and were also effective as vaccines, showing strong cytotoxic T-lymphocyte responses and significant reduction of tumor growth.120 Nanoparticles have been designed to target LNs for vaccination against tumors. The immune-modulator molecule CpG and an adjuvant (ovalbumin) were conjugated onto the surfaces of separate 30-nm polymeric NPs and injected intradermally. Both NP conjugates rapidly drained to the LNs and enhanced the DC cell uptake of both antigen and adjuvant.121 This codelivery strategy induced potent effector CD8+ T cells and a more efficacious memory recall of cytotoxic T cells upon reinjection of tumor cells, compared with the response with NP-conjugated antigen with free adjuvant.

Nanoparticles can be delivered via pulmonary administration to the numerous APCs in the lung, which can take them up avidly.122 A subset of such lung APCs can further transport NPs containing antigens to DCs in draining LNs. In mice vaccinated by pulmonary administration of nanovesicles loaded with antigen and Toll-like receptor agonist that both promote cytotoxic T-cell response,123 the antigen was detected in LNs for at least 7 days, whereas pulmonary immunization with soluble vaccines led to rapid antigen clearance. Strong T-cell responses elicited by this pulmonary vaccine nanovesicle enhanced protective immune responses in tumors.

Cell therapy for cancer immunotherapy (e.g., adoptive transfer of T lymphocytes) represents another promising approach.124 In this approach, immune cells (e.g., T cells) are harvested and manipulated ex vivo with cytokines to stimulate immune cells, then reintroduced into the body. Cytokines used in such therapy may generate systemic toxicity, but it is necessary to maintain a high level near the administered therapeutic cells in order to maintain cell stimulation over an extended period. A new approach to overcome this problem is to directly tether cytokine-loaded NPs to the surfaces of the therapeutic cells prior to infusion (Fig. 4).125 Liposomal NPs containing IL-15Sa and IL-21 were conjugated to thiol groups on the surfaces of T lymphocytes. The NP-tethering strategy greatly enhanced T-cell survival and expansion after infusion and slowed tumor growth (Fig. 4).

Scheme of NP-tethering T cells for adoptive cancer immunotherapy. T cells are linked with NPs containing cytokines that can stimulate the T cells to kill tumor cells. The activated T cells are adoptively transferred in vivo; NPs release cytokines locally to sustainably stimulate T cells to target tumors.

Besides using NPs to deliver antigens or immunotherapeutic agents, NPs can trigger adaptive immune response in tumor. Recently, it was reported that the photothermal ablation of breast tumor using single-walled carbon nanotube can induce the immune response at the tumor site, which is not observed on the condition that tumors are removed by surgical resection.126 The carbon nanotube–based photothermal therapy induced DC maturation in the tumor-draining LNs with elevated cytokines to trigger immune response against tumors. Such photothermal tumor ablation combined with anti–CTLA-4 blockade could effectively enhance immune response against reinjected tumor cells, with increased ratio of cytotoxic CD8+ cells to regulatory T cells in reinjected tumor site.


Cancer nanomedicine is a very rapidly growing field of translational medicine.127 However, overcoming major hurdles in cancer nanomedicine, including NP circulation, biodistribution, tumor targeting, and tumor penetration, requires a better fundamental understanding of the processes involved.5,128 The knowledge of cancer biology and oncology will enhance the rational design of NPs for specific cancers. Effective therapeutics and diagnostics for cancer require delivery to tumors with appropriate temporal resolution to achieve the most favorable pharmacokinetics. Stimulus-responsive drug delivery systems are expected to address this need. Research is needed to develop new strategies to tailor NPs to specific tumor microenvironment, especially to metastatic tumors, which accounts for the majority of cancer deaths.129 The revolution in the understanding of tumor-associated immune system in the past decade may lead to safer and more effective nanomedicine-based immunotherapies. Of note, biocompatibility, toxicity, and numerous formulation issues will remain important for the success of cancer nanomaterials.130


The authors thank Dr Vikash Chauhan (MIT) for discussion and proofreading.


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Cancer immunology; extracellular matrix; nanomedicine; nanoparticle; near-infrared light; photothermal; stimulus-responsive drug delivery; triggered drug delivery; tumor microenvironment; tumor penetration

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