Brazilian Archives of Biology and Technology

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Review - Human and Animal Health • Braz. arch. biol. technol. 68 • 2025 • https://doi.org/10.1590/1678-4324-2025250060 linkcopy

What is the Best Option for Cellular Immunotherapies in Triple-Negative Breast Cancer? A Systematic Review Based on in vitro and in vivo Evidences

Authorship SCIMAGO INSTITUTIONS RANKINGS

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the worst prognosis and highest malignancy. As an alternative treatment, immunotherapy has gained prominence in recent years for its use of components that modulate the patient's own immune system to combat cancer. Although approved therapies using monoclonal antibodies have shown limitations, a more promising alternative for TNBC is the use of immune cells, which have the ability to infiltrate solid tumors and remain in the tumor microenvironment long-term, promoting a localized and effective immune response. The present study proposed a systematic review of cellular immunotherapies currently under investigation for TNBC. The review was registered with PROSPERO (CRD42024591409). Studies were selected using the PRISMA strategy, and the risk of bias in in vivo studies was assessed with the SYRCLE tool. A total of six studies with in vitro and in vivo analyses were included. Among these, 50% evaluated CAR-T therapy (Chimeric Antigen Receptor T Cells), 16.6% CAR-M therapy (Chimeric Antigen Receptor Macrophages), 16.6% dendritic cell vaccines, and 16.6% autologous CD4⁺ T lymphocytes stimulated ex vivo. The in vitro analyses focused on antitumor capacity, cell proliferation, cytokine production, apoptosis, and phagocytosis. For the in vivo analyses, tumor growth, survival, metastasis development, and cellular infiltration were evaluated. All therapies demonstrated promising effects; notably, immunotherapy with autologous CD4⁺ T lymphocytes achieved the greatest tumor reduction among the studied therapies. This review highlights the potential of immune cell-based therapies, particularly CD4⁺ T lymphocytes, emphasizing the need for further research and potential human testing.

Keywords:
Triple-negative breast cancer; immune cells; tumor microenvironment; target therapy.

Triple-negative breast cancer has the worst prognosis and high malignancy.

Immune cell-based immunotherapies are potentially more effective against solid tumors like triple-negative breast cancer (TNBC).

CD4 lymphocyte therapy achieved the greatest tumor reduction among the selected approaches.

Study (author, year, and country)	Immune cell	Experimental model	Target molecule	Type of analysis	Main findings
Zhang et al., 2020, China [²²].	4T1 tumor cell	DC transfected	miRNA 5119	Co-culture, flow cytometry, cell proliferation.	DC vaccines transfected with miR-5119 induce recovery of the immune response in exhausted CD8⁺ T cells and enhance the release of pro-inflammatory cytokines (IL-2, TNF-α and IFN-γ) by exhausted T cells.
Xia et al., 2020, China [¹⁰].	MDA-MB-231-fluc	CAR-T	EGFR	Co-culture, flow cytometry, cell proliferation and cytotoxicity.	EGFR CAR-T cells exhibited high and specific cytotoxicity against TNBC, greater cell proliferation, stimulating the production of pro-inflammatory cytokines such as IL-2, IFN-γ and TNF-α, important for controlling the growth of malignant cells.
Zhang X et al., 2023, China [²³].	MDA-MB-231-Luc-4	CAR-T	B7-H3	Co-culture, flow cytometry, cell proliferation.	BB-trIL2RB-z CAR-T cells showed increased proliferation and activation of T cells, due to the presence of motifs related to STAT3 and STAT5, increased antitumor cytotoxicity against TNBC and increased production of cytokines such as IL-2 and IFN-γ.
Yang et al., 2023, China [²].	MDA-MB-231 and MDA-MB-468	CAR-T	CD24	Co-culture, flow cytometry, cell proliferation, T cell exhaustion.	The results proved that 24BBz, the CAR-T developed, showed high cytotoxicity against TNBC, based on the production of IL-2 and IFN-γ, high specificity of activation and greater cell proliferation.
Duan et al., 2023, China [²⁴].	4T1 tumor cells	CAR-M	VEGFR2	Co-culture, flow cytometry, phagocytosis and apoptosis.	CAR-Ms had increased expression of MHC-II and CD86 against TNBC cells, as well as pro-inflammatory cytokines (TNF-α and IL-6). The CAR-M type HmC showed greater production of TNF-α, showing greater apoptosis activity and less phagocytosis, suggesting polarization towards the M1 phenotype.
Gammelgaard et al., 2024, Denmark [²⁵].	MDA-MB-231	CD4⁺ T helper cells (ALECSAT)	-	Co-culture, flow cytometry, cell predictions, cell expansion, TCR clonotype analysis.	ALECSAT AII therapy led to the expansion of T cells and NK cells, increased the proportion of memory T cells in relation to naive T cells, decreased the viability of TNBC cells, and presented a greater TCR repertoire.

Study (author, year, and country)	Experimental model	Tumor cell line	Tumor cell volume cell/animal	Cell immunoterapv/ volume cell	Target molecule	Administration/ Frequency	Main fidings
Zhang et al., 2020, China [²²].	Female mice model (BALB/c)	4T1 Tumor cell	5×10⁵	DC transfected	miRNA 5119	Intravenous 3 doses	Dendritic cells transfected with miR-5119 led to a decrease in tumor growth, an increase in effector T cells positive for IL-2, TNF-α and IFN-γ with greater cytotoxicity. Furthermore, there was a decrease in T cells positive for inhibitory receptors (PD-1, BTLA) and regulatory T cells (Treg), related to immune suppression.
Xia et al., 2020, China [¹⁰].	Mice model (SCID)	MDA-MB-231-fluc	1×10⁶	CAR-T 2×10⁵ - 2×10⁶	EGFR	Intravenous 6 doses	CAR-T targeted to EGFR decreased tumor growth, prevented lung metastasis, increased infiltration of tumor T cells, maintaining normal serum levels of pro-inflammatory cytokines (IL-6, IL-1β) and did not present damage to other tissues, in addition to not CAR-T infiltration in normal tissues must be demonstrated.
Zhang et al., 2023, China [²³].	Female mice model (NOG)	MDA-MB-231-Luc-4	1×10⁶	CAR-T 1×10⁶	B7-H3	Intravenous 1 dose	CAR-T targeting B7-H3, called B7-H3BB-trIL2RB-z, delayed tumor growth, increased tumor-infiltrating T cells through increased cell proliferation, increased serum levels of IL-2 and IFN-γ, without presenting toxicity or damage to other organs.
Yang et al., 2023, China [²].	Female mice model (BALB/c)	MDA-MB-231 and MDA-MB-468	3×10⁶ 1×10⁷	CAR-T 1×10⁷	CD24	Intravenous and peritumoral 1 dose	CAR-T cells targeting CD24 (24BBz) reduced tumor volume (intravenous and peritumoral), did not change body weight, did not present damage to other organs, achieved greater tumor infiltration of T cells, as well as greater production of GzmB and IFN-γ, which influence the apoptosis of tumor cells. On the other hand, it increased the levels of PD-1, related to the escape of the immune system by tumor cells.
Duan et al., 2023, China [²⁴].	Female mice model (BALB/c)	4T1 tumor cells	5×10⁵	CAR-M 1×10⁶	VEGFR2	Intravenous 3 doses	HmmC-type CAR-M with TLR4 domain was the most efficient in both normal and immunodeficient mice with a reduction in tumor volume after 3 doses, did not change the weight of the animals and did not damage other organs or local blood vessels.
Gammelgaard et al., 2024, Denmark [²⁵].	Female mice model (NOG)	MDA-MB-231	1×10⁶	CD4⁺ T helper cells (ALECSAT) 1×10⁷	-	Intravenous and peritumoral 1 dose	The combination of ALECSAT, an adoptive cell transfer therapy with CD4+ helper T cells, and anti-PDL1 therapy significantly inhibited tumor growth, blocked metastasis, increased activation of pathways associated with the T cell response (IL-2, STAT5, IFN- y and TNF-α) and prolonged the survival of mice.

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Instituto de Tecnologia do Paraná - Tecpar Rua Prof. Algacyr Munhoz Mader, 3775 - CIC, 81350-010 , Tel: +55 41 3316-3054 - Curitiba - PR - Brazil
E-mail: babt@tecpar.br

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