A <i>β</i>-lapachone-loaded iron-polyphenol nanocomplex enhances chemodynamic therapy through cascade amplification of ROS in tumor

A β-lapachone-loaded iron-polyphenol nanocomplex enhances chemodynamic therapy through cascade amplification of ROS in tumor

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Xueying Shi^a^,¹, Xiaoxuan Zhou^b^,¹, Bing Xiao^a^,^c, Hongxia Xu^a, Wei Zhang^a, Hongjie Hu^b, Shiqun Shao^a, Zhuxian Zhou^a, Youqing Shen^a, Xiaodan Xu^a^,^*, Jianbin Tang^a^,^*

Chinese Chemical Letters | 2025, 36(5) : 110178

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Chinese Chemical Letters | 2025, 36(5): 110178

• Communication •

A β-lapachone-loaded iron-polyphenol nanocomplex enhances chemodynamic therapy through cascade amplification of ROS in tumor

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Xueying Shi^a^,¹, Xiaoxuan Zhou^b^,¹, Bing Xiao^a^,^c, Hongxia Xu^a, Wei Zhang^a, Hongjie Hu^b, Shiqun Shao^a, Zhuxian Zhou^a, Youqing Shen^a, Xiaodan Xu^a^,^*, Jianbin Tang^a^,^*

Affiliations

^a Zhejiang Key Laboratory of Smart Biomaterials, ZJU-Hangzhou Global Scientific and Technological Innovation Center, and College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China

^b Department of Radiology, Sir Run Run Shaw Hospital (SRRSH) of School of Medicine, Zhejiang University, Hangzhou 310027, China

^c Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

Published: 2025-05-15 doi: 10.1016/j.cclet.2024.110178

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Abstract

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Chemodynamic therapy (CDT), using Fenton agents to generate highly cytotoxic ^•OH from H₂O₂ has been demonstrated as a powerful anticancer method. However, the insufficient endogenous H₂O₂ in tumor cells greatly limited its therapeutic effect. Herein, we prepared a pH-responsive β-lapachone-loaded iron-polyphenol nanocomplex (LIPN) through a one-pot method. β-Lapachone in LIPN selectively enhanced H₂O₂ concentration in tumor cells, and ferrous ions cascadely generated abundant cytotoxic ^•OH. Therefore, LIPN with cascade amplification of reactive oxygen species (ROS) showed high chemodynamic cytotoxicity in tumor cells, efficiently improving the expression of damage-associated molecular patterns (DAMPs), and exerting strong immunogenic cell death (ICD). As a result, LIPN exhibited efficient tumor inhibition ability in 4T1 subcutaneous tumor model in vivo with great biocompatibility. Additionally, the infiltration of cytotoxic CD8⁺ T lymphocytes and inhibition of regulatory CD4⁺ FoxP3⁺ T lymphocytes in tumors demonstrated the activation of immunosuppressive tumor microenvironment by LIPN-induced ICD. Therefore, this work provided a new approach to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.

Key words

Cascade amplification of ROS / Tumor-selectivity / Chemodynamic therapy / Immunogenic cell death / Enhanced cancer therapy

Cite this Article

Xueying Shi, Xiaoxuan Zhou, Bing Xiao, Hongxia Xu, Wei Zhang, Hongjie Hu, Shiqun Shao, Zhuxian Zhou, Youqing Shen, Xiaodan Xu, Jianbin Tang. A β-lapachone-loaded iron-polyphenol nanocomplex enhances chemodynamic therapy through cascade amplification of ROS in tumor[J]. Chinese Chemical Letters, 2025 , 36 (5) : 110178 - . DOI: 10.1016/j.cclet.2024.110178

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Despite chemotherapy has been widely applied in tumor therapy [1,2], the adverse side effects and unsatisfactory therapeutic outcomes caused by poor tumor selectivity and immunosuppressive tumor microenvironment limit its further development [3-5]. Immunogenic cell death (ICD), which greatly augments tumor immunogenicity via the release of various damage-associated molecular patterns (DAMPs), provides a promising strategy to increase the antitumor immune effect and patient response rates [6-8]. Many chemo-drugs like doxorubicin (DOX) [9], oxaliplatin [10], and shikonin [11] have been proved to induce ICD successfully by elevating cellular reactive oxygen species (ROS) in tumors [12], improving the tumor immunosuppressive microenvironment. However, the ROS generation is still not enough to elicit strong ICD for efficient immunotherapeutic effect.

Chemodynamic therapy (CDT), a new tumor treatment strategy using Fenton or Fenton-like agents to exert toxic hydroxyl radical (^•OH) to kill tumor cells, has been recently proposed [13-20]. Several metal ions including copper, iron, and manganese ions, could act as Fenton agents to transform endogenous H₂O₂ to a stronger oxidizing ^•OH to induce lethal oxidative damage in the tumor [21-24]. For instance, an intelligent nanoreactor that was capable of triggering Fenton reaction with Cu²⁺ was prepared for enhancing the ICD effect and regulating the tumor immune microenvironment, leading to synergistic chemotherapy or photodynamic therapy (PDT)/immunotherapy [22,25,26]. Mao et al. fabricated a nanomedicine through complexation of various polyphenol segments with Fe³⁺ to improve the anticancer capability of Pt(IV) complexes by elevating ^•OH [27]. However, the insufficient endogenous H₂O₂ and limited ^•OH levels in tumor cells greatly compromised treatment outcome. Thus, selectively amplifying intracellular oxidative stress in tumor to further enhance ICD is highly desired.

β-Lapachone (β-LP) has been proved to generate extensive H₂O₂ under the catalysis of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H): quinone oxidoreductase-1 (NQO1) enzyme overexpressed in tumor cells [28]. In this aspect, our previous research about cascade amplification release micelles showed the abundant ROS produced by β-LP could specifically activate the prodrug of DOX in the tumor [29]. Similarly, β-LP was co-delivered with paclitaxel, nitrogen mustard, and camptothecin-based prodrugs to achieve synergistic chemotherapy [30-32]. Therefore, β-LP can be used to selectively amplify H₂O₂ in tumor, which cascadely enhances Fenton reaction in tumor cells to generate toxic ^•OH. As a result, an exaggerated oxidative damage to tumor cells with enhancing ICD effect can be achieved to improve chemotherapy efficacy.

Herein, we constructed a pH-responsive nanocomplex LIPN (β-lapachone-loaded iron-polyphenol nanocomplex) through the coordination of Fe³⁺, tannic acid (TA), and hyaluronic acid modified with dopamine (HA-DA), and the simultaneous encapsulation of β-LP, which achieving cascade amplification of ROS and efficient anticancer efficacy through inducing the immunogenic cell death (Scheme 1). The formed LIPN could accumulate in the tumor through the enhanced permeability and retention (EPR) effect [3], and disassociate to release β-LP, Fe³⁺, and TA in the acidic tumor microenvironment. The released β-LP selectively increased the H₂O₂ level under the efficient catalysis of NQO1 enzyme overexpressed in tumor cells. Meanwhile, the coexistence of excessive TA enables gradual conversion of both the disintegrated Fe³⁺ toward Fe²⁺ [33] and enhanced H₂O₂ would react with generated Fe²⁺ to amplify the generation of ^•OH, further increasing intracellular ROS production and achieving cascade self-amplification to enhance the ability of ICD. Importantly, the cascade amplification of ROS will not happen in normal tissues, because they do not overexpress NQO1, which can avoid the side effect from the treatment. Therefore, this work demonstrated a novel strategy to improve the ICD of chemodynamic therapy through selectively cascade amplification of ROS in cancer cells.

To develop an efficient cascade ROS-generating nanoparticle with immunogenic cell death for cancer therapy, LIPN was fabricated by utilizing the strong coordination effect between Fe³⁺ and polyphenols under the protection of HA-DA, whose degree of dopamine substitution was determined by ¹H NMR to be 38% (Fig. S1a in Supporting information). Transmission electron microscopy (TEM) showed that LIPN was spherical nanoparticle. Dynamic light scattering (DLS) indicated that LIPN has a volume-averaged hydrodynamic diameter of 70 nm and zeta potential of −22.7 mV (Figs. 1a and b, Fig. S1b in Supporting information). After extracting β-LP with acetonitrile, the nanoparticles became hollow nanocapsules with ca. 20 nm shells (Fig. 1c), which indicated the efficient encapsulation of β-LP. The encapsulation content and efficiency of β-LP tested by high-performance liquid chromatography (HPLC) were 21.0% and 34.2%, respectively. The mass ratio of Fe in the nanoparticles characterized by inductively coupled plasma mass spectrometry (ICP-MS) was determined to be 1.6% which was similar to the energy dispersive spectrometer (EDS) result (1.3%, Fig. S2 in Supporting information). Additionally, as shown in Fig. S3 (Supporting information), the iron that existed in LIPN was found to be ferric ions from the examination of X-ray photoelectron spectroscopy (XPS) showing typical binding energy peaks of 716 eV and 725 eV, which were represented for Fe 2p_3/2 and Fe 2p_1/2, respectively [34]. Moreover, LIPN exhibited promising stability in water, phosphate buffered saline (PBS), saline, and 10% serum during 7 days (Fig. S4 in Supporting information). These results indicated that β-LP formed a nanocrystal core by solvent exchange with the adhesion of polyphenol-Fe³⁺ complex successfully. The pH-responsive release profiles of β-LP from LIPN were measured at pH 7.4, 6.5, 5.0, and 4.0, respectively. As shown in Fig. 1d, more rapid release profiles for β-LP were observed at pH 5.0 and 4.0, with about 60% β-LP released under pH 4.0 in 4 h, while β-LP showed a slow-release profile at pH 7.4. This phenomenon could be explained by a pH-dependent coordinated structural dissociation of TA-Fe nanocomplex [35].

TA could act as a reductant in the iron cycling to supply Fe²⁺ as a Fenton agent continuously [36]. As a reduction-oxidation (REDOX) indicator, o-phenanthroline is often used to detect the existence of Fe²⁺ through the formation of an orange complex. Fig. S5 (Supporting information) showed that the appearance of orange solution (Fe²⁺ indicator) validated the deduction process of TA and Fe³⁺. Specifically, the image showed that pH 4.0 was more suitable for TA to reduce Fe³⁺ compared to pH 7.4. The HA-DA was also tested and showed negligible reducing ability. The resultant solution of Fe²⁺ could react with H₂O₂ to induce Fenton reaction and change to colorless at pH 4.0, which proved the consumption of Fe²⁺. On the contrary, when the colorless solution containing Fe²⁺ and H₂O₂ was further added by TA, it turned orange again, demonstrating the continuous supply of Fe²⁺ by TA. Moreover, the resultant Fe²⁺ could react with H₂O₂ to conduct Fenton reaction. Thus, two commonly used free radical indicators, methylene blue (MB) and 3,3′,5,5′-tetramethylbenzidine (TMB), were applied to detect ^•OH generated from LIPN [37]. Considering that ^•OH could induce color fading of MB and rendering of TMB when LIPN existed in an acidic solution containing H₂O₂ which mimicked the tumor microenvironment, the quenching degree of MB significantly increased and the chromogenic degree of TMB rapidly enhanced (Fig. S6 in Supporting information). Specifically, the absorption peak at 644 nm of MB decreased and that at 652 nm of TMB increased dramatically under the conditions of pH 4.0 containing H₂O₂ (Fig. S7 in Supporting information), which demonstrated that LIPN could be dissociated in acidic environments and act as an efficient chemodynamic agent to produce ^•OH in cancer cells. Additionally, we detected the peroxidase (POD)-like specific activity of LIPN. As shown in Fig. S8 (Supporting information), the K_m of LIPN was determined to be 2.7 mmol/L. Compared with the kinetic parameters of other nanozymes (Table S1 in Supporting information), LIPN showed lower K_m, indicating its great POD-like catalytic performance. Meanwhile, we also detected the specific activity of LIPN, which was calculated to be 1252.7 U/g.

As shown in Figs. 1e and f, LIPN could be uptaken by 4T1 cells and the internalization increased with the prolonged incubation time characterized by confocal laser scanning microscopy (CLSM) and flow cytometry. To elucidate the amplified oxidative damage by Fenton reaction to tumor cells, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and hydroxyphenyl fluorescein (HPF) were used to characterize the ROS and ^•OH changes in 4T1 cells after LIPN treatment, respectively. As expected, LIPN-treated 4T1 cells exhibited the strongest ROS and ^•OH fluorescence compared with that incubated with β-LP and β-LP diminished nanoparticles (IPN) (Fig. 2a, Fig. S9 in Supporting information). Due to the enhancement of cellular ^•OH, LIPN showed greater cytotoxicity than β-LP in 4T1 tumor cells with the half maximal inhibitory concentration (IC₅₀) declined from 0.4 µg/mL to 0.2 µg/mL. Meanwhile, the IC₅₀ of LIPN in 293T normal cells was calculated to be 3.1 µg/mL (Figs. 2b and c). The much higher cytotoxicity against 4T1 tumor cells than that against 293T normal cells was because of the overexpressed NQO1 in cancer cells which triggered cascade amplification of the cellular ROS [28]. The results indicated LIPN could act as an efficient chemodynamic agent against tumors with minimal side effect to normal tissue.

Furthermore, typical ICD signals including calreticulin (CRT), high mobility group box 1 (HMGB1), and ATP, caused by LIPN were tested. These DAMPs were proved to facilitate the recruitment, antigen processing, and presentation, which induced significant cytotoxic T cell infiltration [38-40]. As shown in Figs. 2d and e, the LIPN group led to the highest level of CRT translocation, HMGB1 release and ATP secretion, which were about 3.1, 1.3 and 2.8 folds higher than that of the PBS group (Fig. S10 in Supporting information), respectively. The above results were similar to previous findings that LIPN could specifically amplify the cytotoxic effect on tumor cells.

The in vivo tumor inhibition of LIPN was characterized by 4T1 subcutaneous tumor model. All animal experiments were carried out under the protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Zhejiang University (approval No. 20379) in accordance with the institutional guidelines. The tumor-bearing mice were treated by (1) LIPN, (2) β-LP solubilized with hydroxypropyl cyclodextrin (SLP), (3) IPN, and (4) PBS, respectively. The rapid growth of tumors in the mice treated with SLP or IPN implied that the generation of H₂O₂ or ^•OH solely by β-LP or iron-polyphenol nanocomplex had limited tumor therapeutic efficiency. However, the group treated with LIPN exhibited the strongest tumor suppression effect with a tumor growth inhibitory rate of 76.5%, which could be ascribed to the cascade ROS amplification and subsequently chemodynamic damage in tumor cells (Figs. 3a–c). Fig. 3d showed steady body weight in PBS, IPN and LIPN groups rather than SLP group during treatment, however, the SLP group recovered its body weight after drug withdrawal, suggesting LIPN greatly reduced the systemic toxicity of β-LP. After 5 rounds of treatments, hematoxylin and eosin (H&E) staining and routine blood test and blood chemistry analysis were conducted to investigate the biosafety and antitumor activity of LIPN (Figs. S11 and S12 in Supporting information). No obvious physiological damages were found in major organs (liver, heart, lung, spleen, and kidney) of the LIPN group, demonstrating LIPN's great biocompatibility. Additionally, the H&E staining of tumor sections showed that LIPN caused severe damage with cell fragmentation in tumor tissue, and those of the other groups almost had no change. The blood circulation time of β-LP in LIPN was determined with t_1/2(α) of 0.03 h, and t_1/2(β) of 5.03 h, respectively (Fig. S13a in Supporting information). LIPN nanocomplex contained Fe³⁺, which could be used as a magnetic resonance contrast agent for tumor imaging, and the results also showed the effective accumulation in the tumor after 24 h treatment (9.9 µg/g, Figs. S13b and S14 in Supporting information) with good tumor targeting ability. The in vivo ICD effect like the expression of CRT and HMGB1 induced by LIPN in the tumor were also tested by immunofluorescent staining. Compared with the control groups, the LIPN group had significant increased CRT and HMGB1 levels, indicated the chemodynamic therapy with LIPN could efficiently induce ICD (Fig. 3e).

The infiltration of cytotoxic T lymphocytes (CTLs) in tumor-draining lymph nodes (TDLNs) and tumors tissues were characterized by proportions of CD8⁺ cytotoxic T cells and CD4⁺ FoxP3⁺ regulatory T cells (Fig. 4). The LIPN group exhibited the highest increase of CD8⁺ T cells and decrease of CD4⁺ FoxP3⁺ T cells in TDLNs and tumor tissues (Figs. 4a–d). Specifically, the percentages of CD8⁺ T cells in TLDNs and tumor tissues treated by LIPN (44.5%, 23.6%) were higher than that of the PBS group (38.7%, 9.4%). Similarly, the percentage of CD4⁺ Foxp3⁺ T cells in TDLNs and tumors treated by LIPN decreased from 15.9% and 4.6% to 21.8% and 3.7%, respectively, demonstrating an alleviate immune suppression in tumors. The immune-fluorescent staining analysis of tumor sections also demonstrated the highest CD8⁺ T cells recruitment by LIPN treatment (Fig. 4e). Furthermore, the secretion level of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in the serum of the LIPN group were significantly higher than that of the PBS group (Fig. S15 in Supporting information). All these results suggested the enhanced ICD could increase the infiltration of cytotoxic T lymphocytes with decreasing the ratio of regulatory T cells in tumor, and enhance the secretion proinflammatory cytokines, which led to efficient chemodynamic antitumor efficacy of LIPN.

In summary, a pH-responsive LIPN was facilely prepared, which could disassociate in the tumors to release β-LP, Fe³⁺, and TA. The β-LP selectively elevated H₂O₂ in cancer cells and TA reduced Fe³⁺ to Fe²⁺, collectively enhancing the chemodynamic toxicity through Fenton reaction between H₂O₂ and Fe²⁺. LIPN efficiently induced strong ICD reflected by increased translocation of CRT, release of HMGB1 and secretion of ATP. Additionally, LIPN exhibited excellent tumor-targeting capability with the highest accumulation in the tumor. Therefore, LIPN showed efficient anti-tumor activity with a tumor growth inhibitory rate of 76.5% in 4T1 subcutaneous tumor model. The immune analysis suggested that the treatment with LIPN increased the infiltration of CD8⁺ cytotoxic T lymphocytes and decreased the proportion of CD4⁺ FoxP3⁺ regulatory T lymphocytes in tumor tissues, implying the potential synergism of chemodynamic and immune therapy from LIPN. This work demonstrated a method to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.

Declaration of competing interest

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

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Xueying Shi: Writing – review & editing, Methodology, Data curation, Conceptualization. Xiaoxuan Zhou: Resources, Methodology, Data curation. Bing Xiao: Methodology. Hongxia Xu: Software. Wei Zhang: Project administration. Hongjie Hu: Visualization, Funding acquisition. Shiqun Shao: Software, Formal analysis. Zhuxian Zhou: Supervision. Youqing Shen: Visualization, Validation, Methodology. Xiaodan Xu: Writing – original draft, Software, Methodology, Formal analysis, Data curation, Conceptualization. Jianbin Tang: Writing – review & editing, Visualization, Validation, Resources, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Acknowledgments

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This work was financially supported by the National Natural Science Foundation of China (Nos. T2293753, 52203194), the National Key R&D Program of China (No. 2021YFA1201200), the Natural Science Foundation of Zhejiang Province (No. LR18E030002), and 2023 Hangzhou West Lake Pearl Project Leading Innovative Youth Team Project.

Supplementary materials

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Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110178.

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Year 2025 volume 36 Issue 5

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doi: 10.1016/j.cclet.2024.110178

Receive Date：2024-04-28
Online Date：2025-10-29
Published：2025-05-15

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Received：2024-04-28
Revised：2024-06-21
Accepted：2024-06-25

Affiliations

^b Department of Radiology, Sir Run Run Shaw Hospital (SRRSH) of School of Medicine, Zhejiang University, Hangzhou 310027, China

^c Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

Corresponding:

^*E-mail addresses: xuxiaodan@zju.edu.cn (X. Xu), jianbin@zju.edu.cn (J. Tang).

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表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Scheme 1 Schematic illustration of a β-lapachone-loaded iron-polyphenol nanocomplex (LIPN) with cascade amplification of oxidative stress and immunogenic cell death to enhance synergistic chemodynamic and immune cancer therapy.

Fig. 1 (a) TEM image and (b) size of LIPN measured by DLS. (c) TEM image of LIPN after etching with acetonitrile. (d) β-LP release profiles of LIPN under different pH conditions. (e) CLSM image of 4T1 cells incubated with Cy5-labeled LIPN for 1 h. (f) Flow cytometry results of the time-dependent uptake of Cy5-labeled LIPN by 4T1 cells. Data are presented as mean ± standard deviation (SD) (n = 3).

Fig. 2 (a) CSLM images for the cellular ROS and ^•OH of 4T1 cells incubated with PBS, IPN, β-LP, and LIPN, respectively. [β-LP] = 0.5 µg/mL. Relative viabilities of (b) 4T1 cells and (c) 293T cells after LIPN and other treatments with equal β-LP concentration for 48 h. CLSM images of (d) CRT and (e) HMGB1 of 4T1 cells with different treatments. Scale bar: 50 µm. Data are presented as mean ± standard deviation (SD) (n = 3).

Fig. 3 (a) Tumor photo, (b) tumor progression profiles, (c) tumor weight, and (d) body weight of mice bearing 4T1 subcutaneous tumors with different treatments (n = 5). [β-LP] = 5 mg/kg, i.v. with 5 times. (e) Immunofluorescence observation of CRT, HMGB1 in tumor tissues. Scale bar: 200 µm. Data are presented as mean ± SD (n = 3). ***P < 0.001. IRT: tumor growth inhibitory rate.

Fig. 4 Flow cytometry analysis of the percentage of CD3⁺ CD8⁺ T cells in (a) TDLNs and (c) tumor tissues, as well as CD3⁺ CD4⁺ Foxp3⁺ T cells in (b) TDLNs and (d) tumor tissues. (e) Immunofluorescent staining images of CD3⁺ and CD8⁺ T cells in tumor sections after different treatments. Scale bar: 200 µm. Data are presented as mean ± SD (n = 3). P < 0.05, **P < 0.01.

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