The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy

Md Rakibul Alam, Md Mizanur Rahman, Zhiguo Li

Research output: Contribution to journalReview articlepeer-review

6 Scopus citations


Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exosomes to reprogram the factors associated with the tumor microenvironment (TME) causing tumor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with receptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some patients show poor drug response. Exosomal PD-L1 plays a vital role in lowering the treatment response, showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the effect of cell surface PD-L1. To enhance therapeutic response, inhibition of exosomal PD-L1 is required. Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors. Immune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine, nifedipine, lercanidipine, diltiazem, and verapamil were also reported to suppress cellular PD-L1 expression. Therefore, to enhance the PD-1/PD-L1 blockage therapy response, the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consideration. In this review, we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.

Original languageEnglish
Pages (from-to)321-334
Number of pages14
JournalGenes and Diseases
Issue number1
StatePublished - Jan 2024

Bibliographical note

Publisher Copyright:
© 2023 Chongqing Medical University


  • CD8T cells
  • Calcium signaling
  • Exosomal PD-L1
  • Exosomes biogenesis
  • Immunosuppression
  • Immunotherapy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics(clinical)
  • Cell Biology


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