Objective　To systematically review the correlation between cell proliferation nuclear antigen Ki-67 expression and tumor-infiltrating lymphocytes (TILs) level in breast cancer.

Methods　PubMed, Embase and Web of Science databases were systematically searched to collect studies on the correlation between Ki-67 expression level and TILs level in breast cancer from inception to November 30, 2025. Two researchers independently screened literature, extracted data and assessed the risk of bias of included studies. Meta-analysis was performed using RevMan 5.4 software and Stata 17.0 software.

Results　A total of 31 studies involving 13,633 patients with breast cancer were included. Meta-analysis results showed that the proportion of patients with high levels of TILs in the Ki-67 high-expression group was significantly higher than that in the Ki-67 low-expression group [RR=2.02, 95%CI (1.73, 2.36), P < 0.001]. Subgroup analysis showed that the positive correlation between Ki-67 expression level and TILs level remained consistent with the overall Meta-analysis results across different subgroups, including different TILs subtypes, study populations, and sample sizes. Sensitivity analysis indicates that the results of the overall findings of the Meta-analysis was robust.

Conclusion　Current evidence shows that the TILs level is significantly positively correlated with Ki-67 expression level in breast cancer. This finding suggests that the proliferation activity of breast cancer cells may be closely associated with immune activation in the tumor microenvironment, but the above conclusion needs to be verified by more high-quality studies.

1.Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.

2.Siegel RL, Kratzer TB, Wagle NS, et al. Cancer statistics, 2026[J]. CA Cancer J Clin, 2026,76(1): e70043.

3.Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022[J]. J Natl Cancer Cent, 2024, 4(1): 47-53.

4.Onkar SS, Carleton NM, Lucas PC, et al. The great immune escape: understanding the divergent immune response in breast cancer subtypes[J]. Cancer Discov, 2023, 13(1): 23-40.

5.Harris MA, Savas P, Virassamy B, et al. Towards targeting the breast cancer immune microenvironment[J]. Nat Rev Cancer, 2024, 24(8): 554-577.

6.Peura A, Turpin R, Liu R, et al. Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling[J]. Nat Commun, 2025, 16(1): 4908.

7.Xu W, Zhang T, Zhu Z, et al. The association between immune cells and breast cancer: insights from Mendelian randomization and Meta-analysis[J]. Int J Surg, 2025, 111(1): 230-241.

8.Sun HK, Jiang WL, Zhang SL, et al. Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: a systematic review and Meta-analysis[J]. World J Clin On-colhttps://pubmed.ncbi.nlm.nih.gov/39071463/, 2024, 15(7): 920-935.

9.Derouane F, Ambroise J, van Marcke C, et al. Response to neoadjuvant chemotherapy in early breast cancers is associated with epithelial-mesenchymal transition and tumor-infiltrating lymphocytes[J]. Mol Oncol, 2025, 19(8): 2330-2347.

10.Geurts V, Balduzzi S, Steenbruggen TG, et al. Tumor-infiltrating lymphocytes in patients with stage I triple-negative breast cancer untreated with chemotherapy[J]. JAMA Oncol, 2024, 10(8): 1077-1086.

11.Niu R, Wang C, Xie Y, et al. Prognostic significance of CD8+ tumor-infiltrating lymphocytes in operable breast cancer: a Meta-analysis[J]. BMC Cancer, 2025, 25(1): 601.

12.Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast cancer[J]. J Immunother Cancer, 2016, 4: 59.

13.Buisseret L, Garaud S, de Wind A, et al. Tumor-infiltrating lymphocyte composition, organization and PD-1/ PD-L1 expression are linked in breast cancer[J]. Oncoimmunology, 2017, 6(1): e1257452.

14.Denkert C, Loibl S, Müller BM, et al. Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial[J]. Ann On-colhttps://pubmed.ncbi.nlm.nih.gov/23970015/, 2013, 24(11): 2786-2793.

15.Schettini F, Brasó-Maristany F, Pascual T, et al. Identifying predictors of treatment response and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-negative breast cancer: the NEOENDO translational study[J]. ESMO Openhttps://pubmed.ncbi.nlm.nih.gov/39608304/, 2024, 9(12): 103989.

16.Sirvén MB, López-Knowles E, Zhu X, et al. Short-duration preoperative endocrine therapy alters molecular profiles to predict favourable outcome in ER+/HER2+ early breast cancer: a POETIC translational study[J]. EBioMedicine, 2025, 118: 105823.

17.Inwald EC, Klinkhammer-Schalke M, Hofstädter F, et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry[J]. Breast Cancer Res Treat, 2013, 139(2): 539-552.

18.Pan Y, Yuan Y, Liu G, et al. P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients[J]. PLoS One, 2017, 12(2): e0172324.

19.Tőkés T, Tőkés AM, Szentmártoni G, et al. Prognostic and clinicopathological correlations of cell cycle marker expressions before and after the primary systemic therapy of breast cancer[J]. Pathol Oncol Res, 2020, 26(3): 1499-1510.

20.Montagna E, Vingiani A, Maisonneuve P, et al. Unfavorable prognostic role of tumor-infiltrating lymphocytes in hormone-receptor positive, HER2 negative metastatic breast cancer treated with metronomic chemotherapy[J]. Breast, 2017, 34: 83-88.

21.Jang N, Kwon HJ, Park MH, et al. Prognostic value of tumor-infiltrating lymphocyte density assessed using a standardized method based on molecular subtypes and adjuvant chemotherapy in invasive breast cancer[J]. Ann Surg Oncol, 2018, 25(4): 937-946.

22.Chen Y, Klingen TA, Aas H, et al. Tumor-associated lymphocytes and macrophages are related to stromal elastosis and vascular invasion in breast cancer[J]. J Pathol Clin Res, 2021, 7(5): 517-527.

23.Abuhadra N, Sun R, Yam C, et al. Predictive roles of baseline stromal tumor-infiltrating lymphocytes and Ki-67 in pathologic complete response in an early-stage triple-negative breast cancer prospective trial[J]. Cancers (Basel), 2023, 15(13): 3275.

24.Kolberg-Liedtke C, Gluz O, Heinisch F, et al. Association of TILs with clinical parameters, Recurrence Score® results, and prognosis in patients with early HER2-negative breast cancer (BC)-a translational analysis of the prospective WSG PlanB trial[J]. Breast Cancer Res, 2020, 22(1): 47.

25.Schiza A, Thurfjell V, Stenmark Tullberg A, et al. Tumour-infiltrating lymphocytes add prognostic information for patients with low-risk DCIS: findings from the SweDCIS randomised radiotherapy trial[J]. Eur J Cancer, 2022, 168: 128-137.

26.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews[J]. BMJ, 2021, 372: n71.

27.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in Meta-analyses[J]. Eur J Epidemiol, 2010, 25(9): 603-605.

28.Egger M, Davey Smith G, Schneider M, et al. Bias in Meta-analysis detected by a simple, graphical test[J]. BMJ, 1997, 315(7109): 629-634.

29.Dong DD, Yie SM, Li K, et al. Importance of HLA-G expression and tumor infiltrating lymphocytes in molecular subtypes of breast cancer[J]. Hum Immunol, 2012, 73(10): 998-1004.

30.Chung YR, Kim HJ, Jang MH, et al. Prognostic value of tumor infiltrating lymphocyte subsets in breast cancer depends on hormone receptor status[J]. Breast Cancer Res Treat, 2017, 161(3): 409-420.

31.Rao N, Qiu J, Wu J, et al. Significance of tumor-infiltrating lymphocytes and the expression of topoisomerase Ⅱα in the prediction of the clinical outcome of patients with triple-negative breast cancer after taxane-anthracycline-based neoadjuvant chemotherapy[J]. Chemotherapy, 2017, 62(4): 246-255.

32.Watanabe T, Hida AI, Inoue N, et al. Abundant tumor infiltrating lymphocytes after primary systemic chemotherapy predicts poor prognosis in estrogen receptor-positive/HER2-negative breast cancers[J]. Breast Cancer Res Treat, 2018, 168(1): 135-145.

33.Fujimoto Y, Watanabe T, Hida AI, et al. Prognostic significance of tumor-infiltrating lymphocytes may differ depending on Ki67 expression levels in estrogen receptor-positive/HER2-negative operated breast cancers[J]. Breast Cancer, 2019, 26(6): 738-747.

34.Miyoshi Y, Shien T, Ogiya A, et al. Associations in tumor infiltrating lymphocytes between clinicopathological factors and clinical outcomes in estrogen receptor-positive/human epidermal growth factor receptor type 2 negative breast cancer[J]. Oncol Lett, 2019, 17(2): 2177-2186.

35.Zhao X, Li Y, Wang X, et al. Synergistic association of FOXP3+ tumor infiltrating lymphocytes with CCL20 expressions with poor prognosis of primary breast cancer: a retrospective cohort study[J]. Medicine (Baltimore), 2019, 98(50): e18403.

36.Asano Y, Kashiwagi S, Goto W, et al. Predicting therapeutic efficacy of endocrine therapy for stage Ⅳ breast cancer by tumor-infiltrating lymphocytes[J]. Mol Clin Oncol, 2020, 13(2): 195-202.

37.Choi WJ, Kim Y, Cha JH, et al. Correlation between magnetic resonance imaging and the level of tumor-infiltrating lymphocytes in patients with estrogen receptor-negative HER2-positive breast cancer[J]. Acta Radiol, 2020, 61(1): 3-10.

38.Criscitiello C, Vingiani A, Maisonneuve P, et al. Tumor-infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer[J]. Breast Cancer Res Treat, 2020, 183(2): 347-354.

39.Evangelou Z, Papoudou-Bai A, Karpathiou G, et al. PD-L1 expression and tumor-infiltrating lymphocytes in breast cancer: clinicopathological analysis in women younger than 40 years old[J]. In Vivo, 2020, 34(2): 639-647.

40.Genco IS, Ozgultekin B, Hosseini H, et al. High EZH2 expression in ductal carcinoma in situ diagnosed on breast core needle biopsy is an independent predictive factor for upgrade on surgical excision[J]. Pathol Res Pract, 2020, 216(12): 153283.

41.Tang WJ, Jin Z, Zhang YL, et al. Whole-lesion histogram analysis of the apparent diffusion coefficient as a quantitative imaging biomarker for assessing the level of tumor-infiltrating lymphocytes: value in molecular subtypes of breast cancer[J]. Front Oncol, 2020, 10: 611571.

42.Yu H, Meng X, Chen H, et al. Correlation between mammographic radiomics features and the level of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer[J]. Front Oncol, 2020, 10: 412.

43.Feng J, Li J, Huang X, et al. Nomogram to predict tumor-infiltrating lymphocytes in breast cancer patients[J]. Front Mol Biosci, 2021, 8: 761163.

44.Honda C, Kurozumi S, Katayama A, et al. Prognostic value of tumor-infiltrating lymphocytes in estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer[J]. Mol Clin Oncol, 2021, 15(6): 252.

45.Yokotani T, Ikeda N, Hirao T, et al. Predictive value of tumor-infiltrating lymphocytes for pathological response to neoadjuvant chemotherapy in breast cancer patients with axillary lymph node metastasis[J]. Surg Today, 2021, 51(4): 595-604.

46.Yu H, Meng X, Chen H, et al. Predicting the level of tumor-infiltrating lymphocytes in patients with breast cancer: usefulness of mammographic radiomics features[J]. Front Oncol, 2021, 11: 628577.

47.Zhang J, Abubakar M, Yuan P, et al. Prognostic significance of tumor-infiltrating lymphocytes in premenopausal, luminal breast cancer treated with adjuvant endocrine therapy[J]. Am J Transl Reshttps://pubmed.ncbi.nlm.nih.gov/34956490/, 2021, 13(11): 12750-12762.

48.Jia H, Zhao P, Chen Z, et al. Clinicopathological characteristics and prognostic analysis of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ (DCIS) and DCIS with microinvasion (DCIS-Mi) of the breast[J]. Breast Cancer Res Treat, 2022, 193(1): 111-120.

49.Okcu O, Öztürk SD, Öztürk Ç, et al. Tumor-infiltrating lymphocytes (TILs)/volume and prognosis: the value of TILs for survival in HER2 and TN breast cancer patients treated with chemotherapy[J]. Ann Diagn Pathol, 2022, 58: 151930.

50.Sharma R, Elhence PA, Rao M, et al. Crosstalk between programmed death ligand 1, Ki-67 labelling index, and tumor-infiltrating lymphocytes in invasive breast cancer and clinicopathological correlations in a tertiary care center in Western India[J]. Iran J Pathol, 2022, 17(3): 314-322.

51.Duong TT, Pham D, Duong H, et al. Stromal tumor-infiltrating lymphocytes associated with immunohistopathology and molecular subtypes of breast cancer in Vietnam[J]. Asian Pac J Cancer Prev, 2023, 24(7): 2523-2530.

52.Huynh CG, Huynh NX, Truong H, et al. PD-L1 and TILs expression and their association with clinicopathological characteristics in Vietnamese women with primary invasive breast cancer[J]. Medicine (Baltimore), 2023, 102(26): e34222.

53.Sun T, Wang T, Li X, et al. Tumor-infiltrating lymphocytes provides recent survival information for early-stage HER2-low-positive breast cancer: a large cohort retrospective study[J]. Front Oncol, 2023, 13: 1148228.

54.Dieci MV, Radosevic-Robin N, Fineberg S, et al. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer[J]. Semin Cancer Biol, 2018, 52(Pt 2): 16-25.

55.Soysal SD, Tzankov A, Muenst SE. Role of the tumor microenvironment in breast cancer[J]. Pathobiology, 2015, 82(3-4): 142-152.

56.Wu SY, Liao P, Yan LY, et al. Correlation of MKI67 with prognosis, immune infiltration, and T cell exhaustion in hepatocellular carcinoma[J]. BMC Gastroenterol, 2021, 21(1): 416.

57.Schaaf MB, Garg AD, Agostinis P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy[J]. Cell Death Dis, 2018, 9(2): 115.

58.Mempel TR, Lill JK, Altenburger LM. How chemokines organize the tumour microenvironment[J]. Nat Rev Cancer, 2024, 24(1): 28-50.

59.Han B, Han X, Luo H, et al. Multiomics and single-cell sequencings reveal the specific biological characteristics of low Ki-67 triple-negative breast cancer[J]. Cancer Innov, 2024, 3(5): e146.

60.MacNabb BW, Tumuluru S, Chen X, et al. Dendritic cells can prime anti-tumor CD8(+) T cell responses through major histocompatibility complex cross-dressing[J]. Immunity, 2022,55(6):982-997.e8.

61.Jørgensen N, Hviid T, Nielsen LB, et al. Tumour-infiltrating CD4-, CD8- and FOXP3-positive immune cells as predictive markers of mortality in BRCA1- and BRCA2-associated breast cancer[J]. Br J Cancer, 2021,125(10):1388-1398.