The γδ T cells are unconventional lymphocytes that function in both innate and adaptive immune responses against various intracellular and infectious stresses. The γδ T cells can be exploited as cancer-killing effector cells since γδ TCRs recognize MHC-like molecules and growth factor receptors that are upregulated in cancer cells, and γδ T cells can differentiate into cytotoxic effector cells. However, γδ T cells may also promote tumor progression by secreting IL-17 or other cytokines. Therefore, it is essential to understand how the differentiation and homeostasis of γδ T cells are regulated and whether distinct γδ T cell subsets have different functions. Human γδ T cells are classified into Vδ2 and non-Vδ2 γδ T cells. The majority of Vδ2 γδ T cells are Vγ9δ2 T cells that recognize pyrophosphorylated isoprenoids generated by the dysregulated mevalonate pathway. In contrast, Vδ1 T cells expand from initially diverse TCR repertoire in patients with infectious diseases and cancers. The ligands of Vδ1 T cells are diverse and include the growth factor receptors such as endothelial protein C receptor. Both Vδ1 and Vδ2 γδ T cells are implicated to have immunotherapeutic potentials for cancers, but the detailed elucidation of the distinct characteristics of 2 populations will be required to enhance the immunotherapeutic potential of γδ T cells. Here, we summarize recent progress regarding cancer immunology of human γδ T cells, including their development, heterogeneity, and plasticity, the putative mechanisms underlying ligand recognition and activation, and their dual effects on tumor progression in the tumor microenvironment.

Bladder cancer ranks as the 10th most common cancer type globally, and muscle-invasive disease accounts for approximately 25% of newly diagnosed bladder cancers. Despite definitive treatment, 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastasis within 2 years, leading to death. Perioperative systemic therapy is generally recommended to control local relapse or distant metastasis after surgical resection for patients with MIBC. Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the current standard treatment to improve oncologic control and survival outcomes. Adjuvant chemotherapy is recommended for patients with pathological T3-4 or positive lymph nodes after radical cystectomy if no neoadjuvant chemotherapy was given. Nonetheless, perioperative systemic therapy is not applied widely because of its toxicity, and less than 25% of patients receive cisplatin-based neoadjuvant chemotherapy. Therefore, the development of predictive biomarkers for neoadjuvant chemotherapy efficacy and alternative effective regimens for cisplatin-ineligible patients are important. Furthermore, recently, novel anticancer agents such as immune checkpoint inhibitors and antibody-drug conjugates have proven survival benefits in the metastatic setting, thereby expanding their therapeutic applications to the perioperative setting for non-metastatic MIBC. Herein, we discuss the current status and future perspectives of perioperative systemic strategies for MIBC.

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