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Therapeutic potential of tertiary lymphoid structures in breast cancer (Review)

  • Authors:
    • Liangxiao Zhu
    • Meigui Li
    • Feng Liu
    • Fenghou Gao
  • View Affiliations / Copyright

    Affiliations: Clinical Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai 201999, P.R. China, Department of Oncology, Hainan Western Central Hospital, Danzhou, Hainan 571700, P.R. China, Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 177
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    Published online on: April 24, 2026
       https://doi.org/10.3892/mmr.2026.13887
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Abstract

Tertiary lymphoid structures (TLS) are organized immune aggregates within the tumor microenvironment that are associated with improved prognosis and immunotherapy response in breast cancer, yet their functional duality and therapeutic potential require further clarification. The present review comprehensively summarizes current knowledge on TLS in breast cancer, focusing on their molecular mechanisms of formation and maturation, multifaceted functions in anti‑tumor immunity, established prognostic importance and emerging strategies for therapeutic targeting. The present study highlights that mature and functional TLS are key mediators of adaptive anti‑tumor immunity, whereas immature TLS may have opposing effects. Their presence and characteristics hold strong prognostic value and can predict response to immune checkpoint inhibitors. Consequently, therapeutic strategies aimed at inducing or enhancing TLS represent a promising direction for breast cancer immunotherapy. However, further research is needed to elucidate the precise regulatory networks and translate TLS‑focused strategies into clinical practice.
View Figures

Figure 1

Molecular cascade driving TLS
formation in breast cancer. Schematic illustrating that the
formation of TLS is a multi-step process initiated by tumor-derived
DAMPs and neoantigens, which promote a pro-inflammatory
microenvironment rich in cytokines such as TNF-α, IFN-γ, IL-1β and
IL-6. This inflammatory milieu activates stromal cells, including
fibroblasts and endothelial cells. Activated fibroblasts act as
lymphoid stromal organizers by secreting CCL19, CCL21 and CXCL12.
The organizational phase involves a cellular network where LTi
cells interact with LTo cells (including fibroblasts) via the
LTα1β2-LTβR axis, leading to the secretion of homeostatic
chemokines (CXCL13, CCL19 and CCL21). This is reinforced by
adaptive immunity, particularly the Tfh cell/B cell axis, where Tfh
cells (producing CXCL13) provide CD40L and ICOS co-stimulation to B
cells to drive germinal center reactions. Concurrently, LTβR
signaling drives the differentiation of endothelial cells into
specialized HECs. These HECs express PNAd, which interacts with
CD62L on lymphocytes to facilitate homing, a process supported by
VEGF. The spatial organization of infiltrating immune cells is
directed by chemokine gradients: CXCL13 recruits CXCR5+
B cells and Tfh cells to follicles; CCL19 and CCL21 recruit
CCR7+ T cells and DCs to the T cell zone; and CXCL9,
CXCL10 and CXCL11 recruit CXCR3+ T cells and NK cells.
TLS, tertiary lymphoid structures; DAMP, damage-associated
molecular pattern; LTi, lymphoid tissue inducer; LTo, lymphoid
tissue organizer; HEC, high endothelial cells; TME, tumor
microenvironment; LTα, lymphotoxin-α; LTβR, lymphotoxin-β receptor;
Tfh, follicular helper T cell; PNAd, peripheral node addressin; DC,
dendritic cell; NK, natural killer; CXCL, C-X-C motif chemokine
ligand; CCL, C-C motif chemokine ligand; ICOS, inducible T cell
costimulatory; ICOSL, ICOS ligand; CAF, cancer-associated
fibroblast.

Figure 2

Progressive maturation of TLS in
breast cancer. Figure depicting the three-stage evolution of TLS
from initial aggregation to a fully functional, organized ectopic
immune niche. Early stage (aggregate): Diffuse infiltration of
immune cells, including CD3+ T cells, CD20+ B
cells and CD11c+ DCs, is driven by high expression of
the chemokines CXCL13 and CCL19/21. This stage is characterized by
the absence of spatial organization and the presence of only
conventional CD31+ blood vessels lacking the PNAd,
indicating immature lymphocyte homing capacity. Primary stage
(structured): Sustained LTβR signaling drives the formation of
specialized PNAd+ MECA79+ high HEVs,
establishing an efficient portal for lymphocyte entry. Initial
compartmentalization emerges, with CXCR5+ B and T
follicular helper cells beginning to coalesce into a B cell
follicle, while CCR7+ T cells and dendritic cells
organize into an adjacent T cell zone guided by a CCL21 gradient.
Secondary stage (GC-positive): TLS achieves full architectural and
functional maturity. A distinct GC forms within the B cell
follicle, evidenced by expression of AID, the transcriptional
regulator BCL6 and the proliferation marker Ki-67. This results in
the output of IgG+ antibody-secreting plasma cells and
the generation of tissue-resident memory T cells. TLS, tertiary
lymphoid structures; PNAd, peripheral node addressin; DC, dendritic
cell; CXCL, C-X-C motif chemokine ligand; CCL, C-C motif chemokine
ligand; LTβR, lymphotoxin-β receptor; HEV, high endothelial venule;
CCR, C-C motif chemokine receptor; AID, activation-induced cytidine
deaminase; GC, germinal center. FDCs, follicular dendritic
cells.

Figure 3

Dual functional roles of TLS in
breast cancer progression and control. TLS exert opposing effects
on the tumor microenvironment depending on their maturation state.
Immature TLS are structurally disorganized and devoid of germinal
centers. Immature TLS are often enriched in immunosuppressive cell
types such as Tregs and exhibit high expression of inhibitory
molecules (including PD-L1, IL-10 and TGF-β). This milieu inhibits
effector T cell function and fosters an environment that promotes
tumor immune evasion and progression or accompanied by abnormal
angiogenesis promoted by high expression of VEGF. Mature TLS are
highly organized, containing a germinal center that supports
antibody affinity maturation and the generation of plasma cells
secreting high-affinity IgG. Concurrently, mature TLS facilitate
the activation of cytotoxic CD8+ T cells and the
formation of Trm. Through these coordinated adaptive immune
responses, mature TLS effectively mediate tumor cell killing and
immune control (for example, ADCC, CDC and ADCP). The balance
between these divergent functional states markedly influences
clinical outcomes. TLS, tertiary lymphoid structures; Tregs,
regulatory T cells; PD-L1, programmed death ligand 1; Trm,
tissue-resident memory T cells; GC, germinal center; Tfh,
follicular helper T cell; VEGF, vascular endothelial growth factor;
ADCC, antibody-dependent cellular cytotoxicity; ADCP,
antibody-dependent cellular phagocytosis; CDC, complement-dependent
cytotoxicity.

Figure 4

Therapeutic strategies targeting
tertiary lymphoid structures in breast cancer. Schematic outlining
a multi-pronged translational approach to harness TLS for cancer
therapy. Strategies are categorized based on their primary
objective; i) Inducing TLS neogenesis: Aims to initiate de
novo TLS formation in non-inflamed tumors using agonists of key
organizing pathways (such as LTβR and CXCL13) or vascular
normalizing agents (anti-VEGF); ii) modulating TLS function: Seeks
to convert existing TLS into potent anti-tumor hubs by blocking
inhibitory checkpoints (including anti-PD-1), providing
co-stimulatory signals (for example, anti-CD40) or depleting
immunosuppressive cells (such as Tregs); and iii) synergizing with
TLS: Leverages the presence of a functional TLS to enhance the
efficacy of conventional therapies, such as chemo-/radiotherapy
(which release tumor antigens) or cancer vaccines (which provide
specific targets). Collectively, these strategies converge on the
goal of amplifying adaptive anti-tumor immunity, including
high-affinity antibody production and cytotoxic T cell activity, to
ultimately improve clinical outcomes. TLS, tertiary lymphoid
structures; Tregs, regulatory T cells; PD-L1, programmed death
ligand 1; LTβR, lymphotoxin-β receptor; CXCL, C-X-C motif chemokine
ligand; CCR, C-C motif chemokine receptor; ICOS, inducible T cell
costimulatory; TIM-3, T cell immunoglobulin and mucin-domain
containing 3; LAG-3, lymphocyte activation gene 3; PD-1, programmed
cell death protein 1; ICIs, immune checkpoint inhibitors; VEGF,
vascular endothelial growth factor.
View References

1 

Kim J, Harper A, McCormack V, Sung H, Houssami N, Morgan E, Mutebi M, Garvey G, Soerjomataram I and Fidler-Benaoudia MM: Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. 31:1154–1162. 2025. View Article : Google Scholar : PubMed/NCBI

2 

Schumacher TN and Thommen DS: Tertiary lymphoid structures in cancer. Science. 375:eabf94192022. View Article : Google Scholar : PubMed/NCBI

3 

Gago da Graça C, van Baarsen LGM and Mebius RE: Tertiary lymphoid structures: Diversity in their development, composition, and role. J Immunol. 206:273–281. 2021. View Article : Google Scholar : PubMed/NCBI

4 

Teillaud JL, Houel A, Panouillot M, Riffard C and Dieu-Nosjean MC: Tertiary lymphoid structures in anticancer immunity. Nat Rev Cancer. 24:629–646. 2024. View Article : Google Scholar : PubMed/NCBI

5 

Zhao L, Jin S, Wang S, Zhang Z, Wang X, Chen Z, Wang X, Huang S, Zhang D and Wu H: Tertiary lymphoid structures in diseases: Immune mechanisms and therapeutic advances. Signal Transduct Target Ther. 9:2252024. View Article : Google Scholar : PubMed/NCBI

6 

Ruddle NH: From lymphotoxin to tertiary lymphoid structures and beyond. Immunol Rev. 335:e700622025. View Article : Google Scholar : PubMed/NCBI

7 

Goronzy JJ and Weyand CM: Perivascular tertiary lymphoid structures in autoimmune disease. Immunol Rev. 332:e700472025. View Article : Google Scholar : PubMed/NCBI

8 

Peyraud F, Guegan JP, Vanhersecke L, Brunet M, Teyssonneau D, Palmieri L, Bessede A and Italiano A: Tertiary lymphoid structures and cancer immunotherapy: From bench to bedside. Med. 6:1005462025. View Article : Google Scholar : PubMed/NCBI

9 

Fridman WH, Meylan M, Pupier G, Calvez A, Hernandez I and Sautès-Fridman C: Tertiary lymphoid structures and B cells: An intratumoral immunity cycle. Immunity. 56:2254–2269. 2023. View Article : Google Scholar : PubMed/NCBI

10 

Wang Q, Yu Y, Wang C, Jiang Z, Li J, Li X, Huang X, Song Y, Li Z, Tang S and Song C: Heterogeneity of tertiary lymphoid structures predicts the response to neoadjuvant therapy and immune microenvironment characteristics in triple-negative breast cancer. Br J Cancer. 132:295–310. 2025. View Article : Google Scholar : PubMed/NCBI

11 

Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, Yizhak K, Sade-Feldman M, Blando J, Han G, et al: B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 577:549–555. 2020. View Article : Google Scholar : PubMed/NCBI

12 

Munoz-Erazo L, Rhodes JL, Marion VC and Kemp RA: Tertiary lymphoid structures in cancer-considerations for patient prognosis. Cell Mol Immunol. 17:570–575. 2020. View Article : Google Scholar : PubMed/NCBI

13 

Figenschau SL, Knutsen E, Urbarova I, Fenton C, Elston B, Perander M, Mortensen ES and Fenton KA: ICAM1 expression is induced by proinflammatory cytokines and associated with TLS formation in aggressive breast cancer subtypes. Sci Rep. 8:117202018. View Article : Google Scholar : PubMed/NCBI

14 

Park IA, Hwang SH, Song IH, Heo SH, Kim YA, Bang WS, Park HS, Lee M, Gong G and Lee HJ: Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling. PLoS One. 12:e01827862017. View Article : Google Scholar : PubMed/NCBI

15 

Deng S, Chen Y, Song B, Wang H, Huang S, Wu K and Chu Q: Tertiary lymphoid structures in cancer: Spatiotemporal heterogeneity, immune orchestration, and translational opportunities. J Hematol Oncol. 18:972025. View Article : Google Scholar : PubMed/NCBI

16 

Zhang Y, Xu M, Ren Y, Ba Y, Liu S, Zuo A, Xu H, Weng S, Han X and Liu Z: Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application. Mol Cancer. 23:752024. View Article : Google Scholar : PubMed/NCBI

17 

Gu-Trantien C, Migliori E, Buisseret L, de Wind A, Brohée S, Garaud S, Noël G, Dang Chi VL, Lodewyckx JN, Naveaux C, et al: CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. JCI Insight. 2:e914872017. View Article : Google Scholar : PubMed/NCBI

18 

Hutloff A: T Follicular Helper-like cells in inflamed Non-lymphoid tissues. Front Immunol. 9:17072018. View Article : Google Scholar : PubMed/NCBI

19 

Noël G, Fontsa ML, Garaud S, De Silva P, de Wind A, Van den Eynden GG, Salgado R, Boisson A, Locy H, Thomas N, et al: Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity. J Clin Invest. 131:e1399052021. View Article : Google Scholar : PubMed/NCBI

20 

Fan X, Feng D, Wei D, Li A, Wei F, Deng S, Shen M, Qin C, Yu Y and Liang L: Characterizing tertiary lymphoid structures associated single-cell atlas in breast cancer patients. Cancer Cell Int. 25:122025. View Article : Google Scholar : PubMed/NCBI

21 

De Silva P, Garaud S, Solinas C, de Wind A, Van den Eyden G, Jose V, Gu-Trantien C, Migliori E, Boisson A, Naveaux C, et al: FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer. EBioMedicine. 39:226–238. 2019. View Article : Google Scholar : PubMed/NCBI

22 

Wu SY, Zhang SW, Ma D, Xiao Y, Liu Y, Chen L, Song XQ, Ma XY, Xu Y, Chai WJ, et al: CCL19+ dendritic cells potentiate clinical benefit of anti-PD-(L)1 immunotherapy in triple-negative breast cancer. Med. 4:373–393.e8. 2023. View Article : Google Scholar : PubMed/NCBI

23 

Lee H, Lee HJ, Song IH, Bang WS, Heo SH, Gong G and Park IA: CD11c-Positive dendritic cells in Triple-negative breast cancer. In Vivo. 32:1561–1569. 2018. View Article : Google Scholar : PubMed/NCBI

24 

Barb AC, Pasca Fenesan M, Pirtea M, Margan MM, Tomescu L, Melnic E and Cimpean AM: Tertiary lymphoid structures (TLSs) and stromal blood vessels have significant and heterogeneous impact on recurrence, lymphovascular and perineural invasion amongst breast cancer molecular subtypes. Cells. 12:11762023. View Article : Google Scholar : PubMed/NCBI

25 

Song IH, Heo SH, Bang WS, Park HS, Park IA, Kim YA, Park SY, Roh J, Gong G and Lee HJ: Predictive value of tertiary lymphoid structures assessed by high endothelial venule counts in the neoadjuvant setting of triple-negative breast cancer. Cancer Res Treat. 49:399–407. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Sawada J, Hiraoka N, Qi R, Jiang L, Fournier-Goss AE, Yoshida M, Kawashima H and Komatsu M: Molecular signature of tumor-associated high endothelial venules that can predict breast cancer survival. Cancer Immunol Res. 10:468–481. 2022. View Article : Google Scholar : PubMed/NCBI

27 

Yakushi A, Sugimoto M and Sasaki T: Co-expression network and survival analysis of breast cancer inflammation and immune system hallmark genes. Comput Biol Chem. 113:1082042024. View Article : Google Scholar : PubMed/NCBI

28 

Zhao YY, Fan Z, Tao BR, Du ZG and Shi ZF: Density of tertiary lymphoid structures predicts clinical outcome in breast cancer brain metastasis. J Immunother Cancer. 12:e0092322024. View Article : Google Scholar : PubMed/NCBI

29 

Jiang B, Wu Z, Zhang Y and Yang X: Associations between tertiary lymphoid structure density, immune checkpoint inhibitor efficacy in solid tumors: Systematic review and meta-analysis. Front Immunol. 15:14148842024. View Article : Google Scholar : PubMed/NCBI

30 

Xu Y, Liu S, Ling X, Wang F and Qian J: Prognostic value of tertiary lymphoid structures in primary breast cancer and their association with immune microenvironment. APMIS. 133:e701142025. View Article : Google Scholar : PubMed/NCBI

31 

Schettini F, Palleschi M, Mannozzi F, Brasó-Maristany F, Cecconetto L, Galván P, Mariotti M, Ferrari A, Scarpi E, Miserocchi A, et al: CDK4/6-Inhibitors versus chemotherapy in advanced HR+/HER2-Negative breast cancer: Results and correlative biomarker analyses of the KENDO randomized phase II trial. Oncologist. 29:e622–e634. 2024. View Article : Google Scholar : PubMed/NCBI

32 

Sofopoulos M, Fortis SP, Vaxevanis CK, Sotiriadou NN, Arnogiannaki N, Ardavanis A, Vlachodimitropoulos D, Perez SA and Baxevanis CN: The prognostic significance of peritumoral tertiary lymphoid structures in breast cancer. Cancer Immunol Immunother. 68:1733–1745. 2019. View Article : Google Scholar : PubMed/NCBI

33 

Lee HJ, Park IA, Song IH, Shin SJ, Kim JY, Yu JH and Gong G: Tertiary lymphoid structures: Prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer. J Clin Pathol. 69:422–30. 2016. View Article : Google Scholar : PubMed/NCBI

34 

Figenschau SL, Fismen S, Fenton KA, Fenton C and Mortensen ES: Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients. BMC Cancer. 15:1012015. View Article : Google Scholar : PubMed/NCBI

35 

Garaud S, Buisseret L, Solinas C, Gu-Trantien C, de Wind A, Van den Eynden G, Naveaux C, Lodewyckx JN, Boisson A, Duvillier H, et al: Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight. 5:e1296412019. View Article : Google Scholar : PubMed/NCBI

36 

Wang B, Liu J, Han Y, Deng Y, Li J and Jiang Y: The presence of tertiary lymphoid structures provides new insight into the clinicopathological features and prognosis of patients with breast cancer. Front Immunol. 13:8681552022. View Article : Google Scholar : PubMed/NCBI

37 

Liu X, Tsang JYS, Hlaing T, Hu J, Ni YB, Chan SK, Cheung SY and Tse GM: Distinct tertiary lymphoid structure associations and their prognostic relevance in HER2 positive and negative breast cancers. Oncologist. 22:1316–1324. 2017. View Article : Google Scholar : PubMed/NCBI

38 

Shiao SL, Gouin KH III, Ing N, Ho A, Basho R, Shah A, Mebane RH, Zitser D, Martinez A, Mevises NY, et al: Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer. Cancer Cell. 42:70–84.e8. 2024. View Article : Google Scholar : PubMed/NCBI

39 

Lee HJ, Kim JY, Park IA, Song IH, Yu JH, Ahn JH and Gong G: Prognostic significance of Tumor-infiltrating lymphocytes and the tertiary lymphoid structures in HER2-Positive breast cancer treated with adjuvant trastuzumab. Am J Clin Pathol. 144:278–288. 2015. View Article : Google Scholar : PubMed/NCBI

40 

Bai X, Zhou Y, Yokota Y, Matsumoto Y, Zhai B, Maarouf N, Hayashi H, Carlson R, Zhang S, Sousa A, et al: Adaptive antitumor immune response stimulated by bio-nanoparticle based vaccine and checkpoint blockade. J Exp Clin Cancer Res. 41:1322022. View Article : Google Scholar : PubMed/NCBI

41 

Osorio JC, Knorr DA, Weitzenfeld P, Blanchard L, Yao N, Baez M, Sevilla C, DiLillo M, Rahman J, Sharma VP, et al: Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer. Cancer Cell. 43:1902–1916.e9. 2025. View Article : Google Scholar : PubMed/NCBI

42 

Ciavattone NG, Bevoor A, Farfel A, Rehman A, Ho KKY, Rock EC, Chen YC, Luker KE, Humphries BA and Luker GD: Inhibiting CXCR4 reduces immunosuppressive effects of myeloid cells in breast cancer immunotherapy. Sci Rep. 15:52042025. View Article : Google Scholar : PubMed/NCBI

43 

Fang Q, Chen S, Chen X, Zou W, Chen D, Huang Y and Wu C: Mature tertiary lymphoid structure associated CD103+ CD8+ Trm cells determined improved anti-tumor immune in breast cancer. Front Oncol. 15:14804612025. View Article : Google Scholar : PubMed/NCBI

44 

Buisseret L, Garaud S, de Wind A, Van den Eynden G, Boisson A, Solinas C, Gu-Trantien C, Naveaux C, Lodewyckx JN, Duvillier H, et al: Tumor-infiltrating lymphocyte composition, organization and PD-1/PD-L1 expression are linked in breast cancer. Oncoimmunology. 6:e12574522016. View Article : Google Scholar : PubMed/NCBI

45 

Zhang NN, Qu FJ, Liu H, Li ZJ, Zhang YC, Han X, Zhu ZY and Lv Y: Prognostic impact of tertiary lymphoid structures in breast cancer prognosis: A systematic review and meta-analysis. Cancer Cell Int. 21:5362021. View Article : Google Scholar : PubMed/NCBI

46 

Lin Y, Yu Y, Wang Q, Huang K, Guo S, Zhang J, He Y, Yu X, Zhang J, Meng F, et al: Machine learning model for predicting tertiary lymphoid structures and treatment response in triple-negative breast cancer. NPJ PrecisOncol. 9:2162025.

47 

Wu SY, Jin X, Liu Y, Wang ZY, Zuo WJ, Ma D, Xiao Y, Fu T, Xiao YL, Chen L, et al: Mobilizing antigen-presenting mast cells in anti-PD-1-refractory triple-negative breast cancer: A phase 2 trial. Nat Med. 31:2405–2415. 2025. View Article : Google Scholar : PubMed/NCBI

48 

Liu J, Wang Y, Tian Z, Lin Y, Li H, Zhu Z, Liu Q, Su S, Zeng Y, Jia W, et al: Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer. Nat Commun. 13:30112022. View Article : Google Scholar : PubMed/NCBI

49 

Yoshimitsu M, Nakamura M, Kano S, Magara T, Kato H, Sakai A, Sugiyama M, Mizokami M and Morita A: CXCL13 and CCL21 induce tertiary lymphoid structures and enhance the efficacy of immunotherapy for melanoma. Cancer Sci. 116:2075–2085. 2025. View Article : Google Scholar : PubMed/NCBI

50 

Kagamu H: Immunotherapy for non-small cell lung cancer. Respir Investig. 62:307–312. 2024. View Article : Google Scholar : PubMed/NCBI

51 

Wu Z, Zhou J, Xiao Y, Ming J, Zhou J, Dong F, Zhou X, Xu Z, Zhao X, Lei P and Huang T: CD20+CD22+ADAM28+ B cells in tertiary lymphoid structures promote immunotherapy response. Front Immunol. 13:8655962022. View Article : Google Scholar : PubMed/NCBI

52 

Bertucci F, Boudin L, Finetti P, Van Berckelaer C, Van Dam P, Dirix L, Viens P, Gonçalves A, Ueno NT, Van Laere S, et al: Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors. Oncoimmunology. 10:19297242021. View Article : Google Scholar : PubMed/NCBI

53 

Solinas C, Garaud S, De Silva P, Boisson A, Van den Eynden G, de Wind A, Risso P, Rodrigues Vitória J, Richard F, Migliori E, et al: Immune checkpoint molecules on tumor-infiltrating lymphocytes and their association with tertiary lymphoid structures in human breast cancer. Front Immunol. 8:14122017. View Article : Google Scholar : PubMed/NCBI

54 

Acar E, Esendağlı G, Yazıcı O and Dursun A: Tumor-infiltrating Lymphocytes (TIL), tertiary lymphoid structures (TLS), and expression of PD-1, TIM-3, LAG-3 on TIL in invasive and in situ ductal breast carcinomas and their relationship with prognostic factors. Clin Breast Cancer. 22:e901–e915. 2022. View Article : Google Scholar : PubMed/NCBI

55 

Lee HJ, Kim YA, Sim CK, Heo SH, Song IH, Park HS, Park SY, Bang WS, Park IA, Lee M, et al: Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer. Oncotarget. 8:113345–113359. 2017. View Article : Google Scholar : PubMed/NCBI

56 

Kim A, Heo SH, Kim YA, Gong G and Jin Lee H: An examination of the local cellular immune response to examples of both ductal carcinoma in situ (DCIS) of the breast and DCIS with microinvasion, with emphasis on tertiary lymphoid structures and tumor infiltrating lymphoctytes. Am J Clin Pathol. 146:137–144. 2016. View Article : Google Scholar : PubMed/NCBI

57 

Singh S, Lee N, Pedroza DA, Bado IL, Hamor C, Zhang L, Aguirre S, Hu J, Shen Y, Xu Y, et al: Chemotherapy coupled to macrophage inhibition induces T-cell and B-cell infiltration and durable regression in Triple-negative breast cancer. Cancer Res. 82:2281–2297. 2022. View Article : Google Scholar : PubMed/NCBI

58 

Zhao Y, Wang S, Lv S, Liu X, Li W, Song Y, Rong D, Zheng P, Huang H and Zheng H: Combined oral low-dose cyclophosphamide endocrine therapy may improve clinical response among patients with metastatic breast cancer via Tregs in TLSs. Sci Rep. 14:134322024. View Article : Google Scholar : PubMed/NCBI

59 

Wei Z, Lin K, Deng W, Chen Y and Lu Y: Tertiary lymphoid structures are associated with lower axillary residual nodal burden in breast cancer patients after neoadjuvant chemotherapy. Eur J Med Res. 30:12632025. View Article : Google Scholar : PubMed/NCBI

60 

Hou X, Li X, Han Y, Xu H, Xie Y, Zhou T, Xue T, Qian X, Li J, Wang HC, et al: Triple-negative breast cancer survival prediction using artificial intelligence through integrated analysis of tertiary lymphoid structures and tumor budding. Cancer. 130:1499–1512. 2024. View Article : Google Scholar : PubMed/NCBI

61 

Briem O, Källberg E, Kimbung S, Veerla S, Stenström J, Hatschek T, Hagerling C, Hedenfalk I and Leandersson K: CD169+ macrophages in primary breast tumors associate with tertiary lymphoid structures, tregs and a worse prognosis for patients with advanced breast cancer. Cancers (Basel). 15:12622023. View Article : Google Scholar : PubMed/NCBI

62 

Pasca Fenesan MM, Cosma AA, Melnic E, Cimpean AM, Cozma GV and Negru AG: Heterogeneity of the Alpha-smooth muscle actin tumor score in breast cancer cells significantly affects tumor invasiveness, recurrence, and patient survival. Cureus. 16:e759082024.PubMed/NCBI

63 

Thomas N, Garaud S, Langouo M, Sofronii D, Boisson A, De Wind A, Duwel V, Craciun L, Larsimont D, Awada A and Willard-Gallo K: Tumor-infiltrating lymphocyte scoring in Neoadjuvant-treated breast cancer. Cancers (Basel). 16:28952024. View Article : Google Scholar : PubMed/NCBI

64 

Buisseret L, Desmedt C, Garaud S, Fornili M, Wang X, Van den Eyden G, de Wind A, Duquenne S, Boisson A, Naveaux C, et al: Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer. Mod Pathol. 30:1204–1212. 2017. View Article : Google Scholar : PubMed/NCBI

65 

Li C, Clauson R, Bugada LF, Ke F, He B, Yu Z, Chen H, Jacobovitz B, Hu H, Chuikov P, et al: Antigen-clustered nanovaccine achieves Long-term tumor remission by promoting B/CD 4 T cell crosstalk. ACS Nano. 18:9584–9604. 2024. View Article : Google Scholar : PubMed/NCBI

66 

Li K, Ji J, Li S, Yang M, Che Y, Xu Z, Zhang Y, Wang M, Fang Z, Luo L, et al: Analysis of the correlation and prognostic significance of tertiary lymphoid structures in breast cancer: A Radiomics-clinical integration approach. J Magn Reson Imaging. 59:1206–1217. 2024. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Zhu L, Li M, Liu F and Gao F: Therapeutic potential of tertiary lymphoid structures in breast cancer (Review). Mol Med Rep 33: 177, 2026.
APA
Zhu, L., Li, M., Liu, F., & Gao, F. (2026). Therapeutic potential of tertiary lymphoid structures in breast cancer (Review). Molecular Medicine Reports, 33, 177. https://doi.org/10.3892/mmr.2026.13887
MLA
Zhu, L., Li, M., Liu, F., Gao, F."Therapeutic potential of tertiary lymphoid structures in breast cancer (Review)". Molecular Medicine Reports 33.6 (2026): 177.
Chicago
Zhu, L., Li, M., Liu, F., Gao, F."Therapeutic potential of tertiary lymphoid structures in breast cancer (Review)". Molecular Medicine Reports 33, no. 6 (2026): 177. https://doi.org/10.3892/mmr.2026.13887
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu L, Li M, Liu F and Gao F: Therapeutic potential of tertiary lymphoid structures in breast cancer (Review). Mol Med Rep 33: 177, 2026.
APA
Zhu, L., Li, M., Liu, F., & Gao, F. (2026). Therapeutic potential of tertiary lymphoid structures in breast cancer (Review). Molecular Medicine Reports, 33, 177. https://doi.org/10.3892/mmr.2026.13887
MLA
Zhu, L., Li, M., Liu, F., Gao, F."Therapeutic potential of tertiary lymphoid structures in breast cancer (Review)". Molecular Medicine Reports 33.6 (2026): 177.
Chicago
Zhu, L., Li, M., Liu, F., Gao, F."Therapeutic potential of tertiary lymphoid structures in breast cancer (Review)". Molecular Medicine Reports 33, no. 6 (2026): 177. https://doi.org/10.3892/mmr.2026.13887
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