Research ArticleExperimental Studies
Open Access

Inflammation-triggering Engineered Macrophages (MacTriggers) Are Promising Cell-based Therapeutic Avenues for Chemoresistant Solid Tumors

TERUKI NII, TOMA YOSHIMI, KENTA TANITO, SHOICHI HIJII, HARUKA TAKATA, AKIHIRO KISHIMURA, TAKESHI MORI, TATSUHIRO ISHIDA and YOSHIKI KATAYAMA
Anticancer Research April 2025, 45 (4) 1395-1405; DOI: https://doi.org/10.21873/anticanres.17525

Abstract

Background/Aim: Chimeric antigen receptor T-cell therapy has shown efficacy against chemoresistant B-cell leukemia and lymphoma but is limited in solid tumors. This study proposes using inflammation-triggering engineered macrophages (MacTriggers) to target chemoresistant tumors. Intravenous MacTriggers infiltrate tumors, inducing inflammation via tumor necrosis factor-alpha (TNF-α), converting the immunosuppressive microenvironment into an immuno-active state, and enhancing anti-tumor immune responses.

Materials and Methods: DOX-resistant murine colon cancer cells (DOX-Resi) were established by repeated in vivo exposure to DOX. IC50 values and mRNA expression of Abcb1a (encoding P-gp) in WT or DOX-Resi cells were evaluated by qPCR. MacTriggers were engineered to release TNF-α upon sensing tumor-associated arginase 1 (Arg1) activity. BALB/c mice with subcutaneous DOX-Resi tumors received intravenous MacTriggers or DOX. Tumor growth, histological changes, and side effects, including cardiotoxicity, were assessed via tumor volume monitoring, immunohistochemistry, and serum cardiac troponin-I measurement.

Results: DOX-Resi cells had an IC50 value approximately 2.5 times higher than WT cells, with significantly higher Abcb1a expression. MacTriggers significantly suppressed DOX-Resi tumor growth, while DOX showed limited efficacy. MacTrigger administration did not cause severe side effects, unlike DOX, which induced cardiotoxicity.

Conclusion: MacTriggers offer a novel, effective, and safer therapeutic approach for chemoresistant solid tumors, addressing chemotherapy limitations and improving outcomes in drug-resistant cancers.

Keywords:

Introduction

Treatment with classical low molecular weight anticancer drugs, such as cisplatin or doxorubicin (DOX), remains one of the primary strategies in cancer therapy (1). However, repeated administration of these drugs in accordance with established regimens frequently leads to drug resistance in tumor tissues (2). This resistance primarily arises from the expression of drug-efflux proteins, particularly P-glyco-protein (P-gp), which actively transport chemotherapeutic agents out of cancer cells (3). Drug-resistant tumors present significant challenges, including the need for higher doses to achieve therapeutic efficacy, leading to increased risk of adverse effects and limited treatment options (4). Thus, there is an urgent need to establish effective alternative therapies for drug-resistant tumors.

Chimeric antigen receptor (CAR)-T cell therapy, a representative cell medicine, has been clinically applied in cases of drug-resistant cancers because it operates via mechanisms distinct from traditional chemotherapy (5). CARs are engineered synthetic receptors that enable T cells to recognize and eliminate cancer cells expressing specific target antigens (6). CAR-T cells have shown efficacy in treating chemoresistant B-cell leukemia or lymphoma (7). However, their effectiveness in solid tumors remains limited, mainly because the immunosuppressive tumor microenvironment hinders CAR-T cell infiltration and reduces their cytotoxic activity upon access. This limited access and rapid functional decline of CAR-T cells in solid tumors results in low anti-tumor efficacy (8). Consequently, there is a critical need to develop novel cell-based therapeutics that can achieve robust therapeutic effects in drug-resistant solid tumors.

We recently reported a novel cell-based therapeutic approach, which utilizes engineered macrophages called MacTriggers (9). Macrophages naturally accumulate within solid tumors in response to tumor-secreted chemokines, such as C-C motif chemokine ligand 2 or granulocyte-macrophage colony-stimulating factor (10). Upon accumulation, macrophages are polarized from the M0 to the M2-like (anti-inflammatory) phenotype, expressing several immunosuppressive genes or proteins that contribute to the tumor’s immunosuppressive conditions (11). Leveraging these innate macrophage properties, we prepared MacTriggers that are genetically modified macrophages designed to release tumor necrosis factor-alpha (TNF-α) in response to arginase 1 (Arg1) activity, a marker uniquely expressed by M2 macrophages. Administered MacTriggers can infiltrate solid tumors and trigger acute inflammation via TNF-α release. This inflammatory response switches immunosuppressive tumor tissues to an immune-activate state, recruiting natural killer cells or cytotoxic T cells to attack the tumor and thereby exert anti-tumor effects. Importantly, MacTriggers that inadvertently accumulate in normal tissues do not polarize to the M2 phenotype, preventing unnecessary TNF-α release and inflammation; thus, damage to normal tissues is avoided (9). MacTriggers present as a powerful cell-based therapy that mediates anti-tumor immunity with minimal risk to normal tissues.

In this study, we investigated the effects of MacTriggers on chemoresistant solid tumors, focusing on overcoming the limitations of current CAR-T cell therapy. MacTriggers were intravenously administered to mice bearing DOX-resistant tumors, and anti-tumor effects and side effects were evaluated. Our findings highlight MacTriggers as a promising new therapeutic option for cancer patients with chemoresistant tumors.

Materials and Methods

Materials. Dulbecco’s Modified Eagle Medium (DMEM), Roswell Park Memorial Institute-1640 (RPMI-1640) medium, antibiotic-antimycotic mixed stock solution, 4% paraformaldehyde phosphate-buffer (4%-PFA PB), Hanks’ Balanced Salt Solution (HBSS), and Dulbecco’s phosphate-buffered saline (PBS) were purchased from Nacalai Tesque, Inc. (Kyoto, Japan). Fetal bovine serum (FBS) was purchased from Nichirei Biosciences, Inc. (Tokyo, Japan). Lipofectamine 3000 and SuperScript III First-Strand Synthesis System were purchased from Thermo Fisher Scientific, Inc. (Waltham, MA, USA). NucleoBond Xtra Maxi Plus EF, In-Fusion Snap Assembly Master Mix, and RNAiso Plus were purchased from Takara Bio, Inc. (Shiga, Japan). G418 sulfate was purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). TritonX-100 was purchased from Sigma Aldrich Co. (St. Louis, MO, USA). Cell Counting Kit-8 (CCK-8) was purchased from Dojindo Laboratories (Kumamoto, Japan). The LightCycler FastStart DNA Master SYBR Green Kit was purchased from Roche Diagnostics (Basel, Switzerland). Tumor dissociation kit (mouse) was purchased from Miltenyi Biotec (Bergisch Gladbach, Germany). Brilliant violet (BV) 421-labeled anti-mouse CD45 antibody, phycoerythin (PE)-labeled anti-mouse TCRβ antibody, Alexa Fluor 488-labeled anti-mouse CD8a antibody, allophycocyanin (APC)-labeled anti-mouse NK1.1 antibody, Enzyme-Linked Immunosorbent Assay (ELISA) MAX™ Deluxe Set Mouse TNF-α, and Stop Solution for TMB Substrate were purchased from BioLegend, Inc. (San Diego, CA, USA). Ki-67 (D3B5) Rabbit mAb was purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA). Horseradish peroxidase (HRP)-labeled rabbit antibody and 3, 3-diaminobenzidine (DAB) were purchased from Dako, Inc. (Glostrup, Denmark). Doxorubicin hydrochloride was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). A goldenrod animal lancet was purchased from MEDIpoint, Inc. (Mineola, NY, USA). Mouse Cardiac Troponin-I (cTnI) ELISA kit was purchased from Life Diagnostics, Inc. (West Chester, PA, USA). All other chemicals were of the highest grade commercially available.

Cell culture. RAW264.7 murine macrophages were purchased from American Type Culture Collection (ATCC; Manassas, VA, USA). Wild-type (WT) Colon-26 murine colon cancer cells were purchased from RIKEN BRC cell bank (Ibaraki, Japan). RAW264.7 cells were cultured in DMEM, and Colon-26 cells were cultured in RPMI-1640. All media was supplemented with 10% heat-inactivated FBS and 1% antibiotic-antimycotic mixed stock solution. Cells were cultured in an atmosphere containing 5% CO2 and 95% air at 37°C.

Preparation of DOX-resistant Colon-26 cells. Animal experiments were performed with approval from the Animal and Ethics Review Committee of Tokushima University (T2022-36). BALB/c mice, 6 weeks old, were purchased from Japan SLC (Shizuoka, Japan). After a week of breeding, colon-26 cells (WT) (2×106 cells in 100 μl PBS) were subcutaneously (s.c.) injected into the back. When the tumor volume reached 100-200 mm3, Doxil (2.5 mg/kg) was administered via a tail vein. After the tumor volume exceeded 1,300 mm, the mice were sacrificed, and the tumor was collected. Then, 150 mg of tumors were placed in 5 ml Krebs-Ringer-Buffer (KRB) containing 2.1 mM CaCl2, 2.1 mM MgCl2, 250 units/ml Collagenase Type IV (Worthington Biochemical Corporation, Lakewood, NJ, USA), and 60 units/ml DNaseI (Roche, Basel, Switzerland) in C-tubes (Miltenyi Biotec). Then, the tumors were dissociated with gentleMACS™ Dissociator (Miltenyi Biotec). The obtained cell suspensions were further incubated at 37°C for 30 min for degradation with collagenase. After incubation, the cell suspensions were further dissociated with gentleMACS™ Dissociator and then passed through a 100 μm mesh of a cell strainer (Greiner Bio-One, Kremsmünster, Austria). The obtained cell suspension was washed by centrifugation at 300 × g at 4°C for 7 min and resuspended in cold PBS. The obtained cells were cultured in RPMI medium. Subsequently, the cells were passaged twice and used in the following experiments. We named DOX-resistant colon-26 cells as DOX-Resi.

Cell viability assay. Colon-26 cells (WT) or DOX-Resi cells were seeded at a density of 8×103 cells/well with 200 μl medium in 96-well plates. After 24 h incubation, 10−11-10−4 M DOX was added to each well. Two days later, the viability was evaluated using CCK-8 according to the manufacturer’s protocol. Absorbance at 450 nm was measured using the Infinite® 200 PRO M Plex (TECAN, Kanagawa, Japan), and cell viability was calculated using the following formula:

Embedded Image

A0: Absorbance without cells and DOX; A1: Absorbance with cells and DOX; A2: Absorbance with cells and without DOX.

Additionally, IC50 values were analyzed using GraphPad Prism software (GraphPad Software, San Diego, CA, USA) (12).

Gene expression analysis. mRNA expression of ATP-binding cassette sub-family B member 1A (Abcb1a, which encodes P-gp) in WT cells or DOX-Resi cells was evaluated using qPCR. WT or DOX-Resi cells were seeded at a density of 1×106 cells/well in 6-well plates in 2.5 ml medium. After 24 h incubation, total RNA was extracted using RNAiso Plus according to the manufacturer’s protocol. Subsequently, reverse transcription of 5 μg RNA was performed using the SuperScript III First-Strand Synthesis System. PCR amplification reactions were performed using the LightCycler FastStart DNA Master SYBR Green kit, and the following PCR conditions were used: 95°C for 10 min, followed by 40 cycles of 95°C for 10 s, 60°C for 10 s, and 72°C for 10 s. Glyceraldehyde-3-phosphate dehydrogenase (Gapdh) was used as a housekeeping gene, and the relative amounts of target gene expression were determined by the comparative CT method. The primer sequences for Abcb1a and Gapdh are shown in Table I.

View this table:
Table I.

Primer list for qPCR.

Preparation of MacTriggers. MacTriggers were prepared according to our previous report (13). Plasmid DNA that expresses TNF-α upon activation of the Arg1 promoter was prepared using In-Fusion Snap Assembly Master Mix in accordance with the manufacturer’s protocol. Plasmid extraction was performed using NucleoBond Xtra Maxi Plus EF. Then, RAW264.7 cells were seeded into 24-well plates at a density of 2×105 cells/well. After the incubation for 24 h, the plasmid was transfected using Lipofectamine3000. After 72 h, the selection of stably-expressing cells was performed using G418 (400 μg/ml), and single-cell cloning was performed in accordance with the general limiting dilution protocol. The expression of TNF-α upon activation of the Arg1 promoter was confirmed using ELISA MAX™ Deluxe Set Mouse TNF-α according to the manufacturer’s protocol.

Evaluation of anti-tumor effects in tumor-bearing mice. Animal experiments were performed with approval from the Institutional Animal Care and Use Committee of Kyushu University (A24-175-1). Female BALB/cAJcl mice aged 5–7 weeks were obtained from Kyudo Japan (Saga, Japan). After a week of acclimation, WT or DOX-Resi cells (2×105 cells in 50 μl HBSS) were s.c. injected into the backs of mice. Five days after tumor inoculation, PBS (100 μl), DOX (2.5 mg/kg in 100 μl PBS), or MacTriggers (1×106 cells in 100 μl PBS) were administered via a tail vein. Additionally, the same dose of DOX was administered via a tail vein in the DOX-treated group on days 4, 8, and 12 (Figure 1A). Then, 14 days after the first treatment, blood was collected using an animal lancet. Tumor volumes and body weights were measured every two days. Tumor volumes were calculated using the following formula:

Figure 1.
Figure 1.

In vitro evaluation of doxorubicin (DOX)-resistant cancer cells. (A) Cell viability and IC50 values of DOX in Colon-26 wild-type (WT) and DOX-resistant (DOX-Resi) cells. (B) ATP-binding cassette sub-family B member 1A (Abcb1) mRNA expression in Colon-26 WT and DOX-Resi cells [n=5, mean (SEM)].

Embedded Image

When the tumor’s major axis reached 20 mm (humane endpoint), the experiment was stopped, and the mice were killed. Several tissues (tumor, liver, spleen, kidney, lung, and heart) were harvested. The weights of the liver and spleen were measured to evaluate inflammation-related tissue enlargement. Cardiac Troponin-I (cTnI) concentration in the collected blood was analyzed using a Mouse cTnI ELISA kit following the manufacturer’s protocol.

Tissue staining. To evaluate adverse effects in normal tissue, hematoxylin and eosin (H&E) staining was performed according to the standard protocol. Fourteen days after the first drug administration, several tissues (liver, spleen, kidney, lung, and heart) were harvested and fixed in 4%-PFA PB. For H&E staining, several tissues were deparaffinized and washed with water. Hematoxylin was added and incubated for 5 min, and the slides were washed and hydrated. Eosin was added and incubated for 5 min. Subsequently, the slides were washed. Additionally, immunohistochemistry (IHC) was performed to investigate the proliferation of cancer cells. The tumor tissues were harvested and fixed in 4%-PFA PB. For IHC, sections embedded in paraffin blocks were used for Ki67 staining. Tumor tissues were deparaffinized, hydrated, and heated in citric acid buffer (pH 6.0) to 95°C for 15 min, then blocked with 3% skim milk for 10 min. Then, the slides were incubated overnight with an anti-Ki67 antibody (1:200). After incubation, the slides were washed with PBS and incubated with 0.3% hydrogen peroxide-methanol buffer for 30 min to block endogenous peroxidase activity. After washing with PBS, HRP-labeled secondary antibody was added and incubated for 30 min. The slides were washed with PBS, and DAB was added as an enzyme substrate. All H&E and IHC section images were observed using a fluorescence microscope (BZ-X800; KEYENCE, Osaka, Japan).

Statistical analysis. GraphPad software was used for all statistical analyses. Two-way analysis of variance (ANOVA) followed by Tukey’s post hoc test was used for multiple comparisons. A two-tailed Welch’s t-test was used for single comparisons. The symbols *, **, and *** indicate p-values less than 0.05, 0.01, and 0.005, respectively, while n.s. indicates no significant differences.

Results

In vitro evaluation of DOX-resistant cancer cells. First, we evaluated the in vitro viability of WT and DOX-Resi cells following DOX treatment using the WST-8 assay. As shown in Figure 1A, IC50 values of DOX were 185.2 nM and 491.9 nM for WT and DOX-Resi, respectively. The IC50 value of DOX in DOX-Resi was approximately 2.5 times higher than that in WT cells, confirming the DOX resistance of the cancer cells in this study. Next, to investigate the mechanism behind DOX resistance, we assessed the expression level of the Abcb1a gene in DOX-resistant cancer cells using qPCR. Abcb1a expression was significantly higher in DOX-Resi than in WT cells, indicating that the acquired resistance due to elevated Abcb1a expression was nearly the same as clinical chemoresistance (Figure 1B). Thus, we can conclude that the DOX-Resi cells prepared in this study are well-suited for research into tumor chemoresistance.

In vivo anti-tumor effects of MacTriggers against DOX-resistance tumors. Following the observation of DOX resistance in cancer cells in vitro (Figure 1), we assessed the anti-tumor effects of MacTriggers in tumor-bearing mice. As shown in Figure 2B, DOX treatment effectively suppressed growth of WT tumors but had a limited impact on DOX-Resi tumors. Conversely, MacTriggers showed significant anti-tumor effects in both WT and DOX-Resi tumors. These findings were further supported by histological analysis, where H&E staining (Figure 2C) and Ki-67 expression patterns (Figure 2D) in tumor sections revealed marked tumor suppression and reduced Ki-67 positivity in both DOX and MacTrigger treatments in WT tumors. In contrast, DOX treatment did not yield similar outcomes in DOX-Resi tumors, whereas MacTriggers consistently showed this tendency. While body weight changes were comparable between the DOX and MacTrigger groups (Figure 2E), MacTriggers extended the survival period of mice with DOX-Resi tumors (Figure 2F).

Figure 2.
Figure 2.
Figure 2.

Anti-tumor effect of MacTriggers in tumor-bearing mice. (A) Schematic of the experimental design. Doxorubicin (DOX) was administered every four days to the DOX-treated group (red dot). (B) Time course of tumor volume over 14 days and image of tumor tissues 14 days after administration of phosphate-buffered saline (PBS), DOX, and MacTriggers [n=5, mean (SEM)]. (C) H&E-stained tumor sections excised from tumor-bearing mice 14 days after administration of PBS, DOX, and MacTriggers. Images were obtained under a microscope using 20×objective. Scale bar, 100 μm. (D) Ki-67-stained tumor sections excised from tumor-bearing mice for 14 days after administration of PBS, DOX, and MacTriggers. Images were obtained with a microscope using the 20× objective. Scale bar, 100 μm. (E) Change in body weight [n=5, mean (SEM)]. (F) Survival rates of mice in each group (n=5, mean (SEM)). Statistical analyses were performed using Student’s t-test. *p<0.05, **p<0.01, ***p<0.005.

Side-effects of MacTriggers against DOX-resistant tumors in vivo. We measured the weight of the liver and spleen because MacTriggers tend to accumulate in these organs. No injury-related tissue enlargement was observed in mice with either WT or DOX-Resi tumors (Figure 3A and B). Additionally, we performed H&E staining on several representative organs (heart, liver, spleen, kidney, and lung) to assess potential adverse effects. The staining revealed no inflammation-related immune cell infiltration in either group (Figure 3C). However, in the DOX-treatment group, we observed loss of myocardial fibers and vacuolation, which are indicators of cardiotoxicity (14). In addition, cTnI levels in the blood, a marker for cardiotoxicity, were also elevated (Figure 3D).

Figure 3.
Figure 3.
Figure 3.

Evaluation of side-effects of MacTriggers. (A) Liver weight/body weight in Wild-type (WT) and doxorubicin (DOX)-resistant (DOX-Resi) cell inoculated animals [n=5, mean (SEM)]. (B) Spleen weight/body weight in WT and DOX-Resi cell inoculated animals [n=5, mean (SEM)]. (C) H&E-stained sections excised from tumor-bearing mice 14 days after administration of phosphate-buffered saline (PBS), DOX, and MacTriggers. Images were obtained with a microscope using the 40× objective. Scale bar, 20 μm. (D) Serum concentration of Cardiac Troponin-I (cTnI). Blood was collected 14 days after first administration of PBS, DOX, and MacTriggers.

Discussion

In this study, we selected 1×106 MacTriggers based on previous optimization experiments that showed practical antitumor effects with minimal side effects (9), making this dose comparable to clinically applied CAR-T cell levels (15, 16). MacTriggers showed potent anti-tumor effects against both DOX-resistant and nonresistant tumors, while DOX treatment alone did not inhibit tumor growth effectively. Importantly, MacTrigger treatment showed no adverse effects on normal tissues, contrasting with DOX treatment, which resulted in cardiotoxicity. These side effects were present not only in WT but also in DOX-Resi tumors despite the insufficient anti-tumor effect of DOX treatment. These results indicate that cancer patients with chemoresistant tumors could experience severe side effects from chemotherapy without achieving adequate anti-tumor efficacy. This situation reflects a significant issue with current chemotherapy (17). In contrast, MacTriggers exhibited consistent anti-tumor effects while having no adverse effects on normal tissues. These findings suggest that MacTriggers could address the limitations of current therapies for chemoresistant tumors, whereby patients often suffer from severe side effects due to continued use of conventional anticancer drugs despite limited anti-tumor efficacy.

Conclusion

This study proposes a novel therapeutic approach to treat chemoresistant solid tumors. MacTriggers demonstrated strong anti-tumor effects against both DOX-resistant and non-resistant tumors, whereas DOX treatment alone failed to suppress tumor growth effectively. Notably, MacTriggers treatment did not cause adverse effects in normal tissues, in contrast to DOX, which induced cardiotoxicity regardless of chemoresistance. These findings suggest that MacTriggers could overcome the limitations of existing therapies for chemoresistant tumors, where patients endure severe side effects due to the prolonged use of conventional anti-cancer drugs despite their limited efficacy. Future research will focus on optimizing MacTriggers for clinical application, aiming to establish a new standard in treating resistant solid tumors.

Acknowledgements

The Authors thank Mr. Hiroshi Fujii for the tissue staining and H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the study’s conception and design. Material preparation: Teruki Nii, Toma Yoshimi, Kenta Tanito, Shoichi Hijii, and Haruka Takata; data collection: Teruki Nii, Toma Yoshimi, Kenta Tanito, Shoichi Hijii, and Haruka Takata; data analysis: Teruki Nii, Toma Yoshimi, Kenta Tanito, Shoichi Hijii, Akihiro Kishimura, Takeshi Mori, Tatsuhiro Ishida, and Yoshiki Katayama. The first draft of the manuscript was written by Teruki Nii, Toma Yoshimi, Kenta Tanito, and Yoshiki Katayama. All Authors commented on previous versions of the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors have no relevant financial or non-financial interests to disclose.

  • Funding

    This work was in part supported by the program on open innovation platform for industry-academia co-creation (Grant No. JPMJPF2107), JSPS KAKENHI (Grant No. JP21K20517, JP22K18197, JP20H05876, JP24K21087, and JP24K21251), a research grant from The Uehara Memorial Foundation (No. 202310209), Terumo Life Science Foundation (No. 23-III2034), Mochida Memorial Foundation For Medical And Pharmaceutical Research, and The Iketani Science and Technology Foundation (No. 0361055-A). In addition, this research was also supported by AMED under Grant Number 24ym0126811j0003, and Center for Clinical and Translational Research of Kyushu University. This research was also supported by AMED under Grant Number 24ck0106966h0001.

  • Received February 18, 2025.
  • Revision received March 4, 2025.
  • Accepted March 5, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Inflammation-triggering Engineered Macrophages (MacTriggers) Are Promising Cell-based Therapeutic Avenues for Chemoresistant Solid Tumors
TERUKI NII, TOMA YOSHIMI, KENTA TANITO, SHOICHI HIJII, HARUKA TAKATA, AKIHIRO KISHIMURA, TAKESHI MORI, TATSUHIRO ISHIDA, YOSHIKI KATAYAMA
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