• Combining Adhesion Molecule and Immune Checkpoint Targeting in TNBC: Mechanisms and Treatment Potential
  • Parnian Fakour,1,*
    1. Department of Immunology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran


  • Introduction: Cancer remains one of the leading causes of mortality worldwide and is strongly associated with the ability of tumor cells to actively remodel the tumor microenvironment (TME). Within this process, epithelial–mesenchymal transition (EMT) contributes not only to enhanced invasion and metastasis but also to the reprogramming of adhesion molecule expression and the upregulation of immune checkpoint inhibitors. These alterations support tumor survival, immune evasion, and resistance to immunotherapies. The present study highlights the importance of these molecules in breast cancer progression.
  • Methods: This review was based on a systematic literature search in PubMed and Google Scholar using the keywords “cancer,” “malignancy,” “metastasis,” “adhesion molecules,” “N-cadherin,” “immune checkpoint molecules,” “PD-1,” and “PD-L1.” Articles were screened for relevance by title, abstract, and full text, and selected studies were included in the review.
  • Results: Recent findings indicate that N-cadherin, as a key marker of epithelial–mesenchymal transition (EMT), plays a critical role in breast cancer progression, particularly in the triple-negative breast cancer (TNBC) subtype. This molecule regulates cell adhesion, thereby facilitating cellular migration and metastasis, and its upregulation contributes to drug resistance, notably against mitoxantrone. Emerging therapeutic studies have demonstrated that inhibition of N-cadherin and EMT can enhance treatment response. Furthermore, as disease severity increases, the expression of immune checkpoint molecules such as PD-1 and PD-L1 is elevated, correlating with disease progression. Targeting these pathways, especially in TNBC, has been shown to strengthen anti-tumor responses. Specifically, intracellular CD28 inhibition reduces PD-L1 expression while enhancing the infiltration and activation of CD8⁺ T cells and Th1 cells. The combination of PD-1/PD-L1 inhibitors with anti-angiogenic agents exhibits synergistic effects, offering novel therapeutic strategies for TNBC. Additional studies have indicated that combining CD300c antibody with PD-1 blockade can remodel the tumor microenvironment, suppress tumor growth and metastasis, increase M1 macrophage infiltration, and enhance T and NK cell activation. Moreover, increased N-cadherin expression has been reported to coincide with elevated PD-L1 levels, whereas N-cadherin depletion results in reduced expression of these immunosuppressive molecules. These findings highlight the complex interplay between EMT and immune checkpoint pathways in tumor immune evasion. Consequently, targeting N-cadherin as an upstream regulator may enhance the efficacy of immunotherapy through concomitant modulation of PD-L1. Overall, the simultaneous assessment of adhesion markers and immune checkpoint molecules is not only valuable for predicting disease severity but also targeting these pathways can effectively reduce metastasis, inhibit EMT, and preserve anti-tumor immune cell function. Specifically, N-cadherin inhibition can attenuate EMT and downregulate PD-L1 expression, thereby maintaining cytotoxic T cell activity.
  • Conclusion: Overall, Findings indicate that simultaneous inhibition of N-cadherin and the PD-1/PD-L1 pathway can exert a significant synergistic effect in reducing metastasis, stabilizing the tumor microenvironment, and enhancing the antitumor activity of the immune system. These two pathways are functionally interconnected, with N-cadherin acting as a direct regulator of PD-L1 expression. Consequently, their combined blockade represents a promising strategy to improve the efficacy of anticancer therapies, .particularly in aggressive cancers such as TNBC.
  • Keywords: Breast Cancer / TTNBC / Immune Checkpoint Molecules / N-cadherin / Therapeutic Targeting