The molecules of Major histocompatibility class I (MHC-I) load peptides and present them on the cell surface, which provided the immune system with the signal to detect and eliminate the infected or cancerous cells. In the context of cancer, owing to the crucial immune-regulatory roles played by MHC-I molecules, the abnormal modulation of MHC-I expression and function could be hijacked by tumor cells to escape the immune surveillance and attack, thereby promoting tumoral progression and impairing the efficacy of cancer immunotherapy. Here we reviewed and discussed the recent studies and discoveries related to the MHC-I molecules and their multidirectional functions in the development of cancer, mainly focusing on the interactions between MHC-I and the multiple participators in the tumor microenvironment and highlighting the significance of targeting MHC-I for optimizing the efficacy of cancer immunotherapy and a deeper understanding of the dynamic nature and functioning mechanism of MHC-I in cancer.

Cells, as the fundamental units of life, contain multidimensional spatiotemporal information. Single-cell RNA sequencing (scRNA-seq) is revolutionizing biomedical science by analyzing cellular state and intercellular heterogeneity. Undoubtedly, single-cell transcriptomics has emerged as one of the most vibrant research fields today. With the optimization and innovation of single-cell sequencing technologies, the intricate multidimensional details concealed within cells are gradually unveiled. The combination of scRNA-seq and other multi-omics is at the forefront of the single-cell field. This involves simultaneously measuring various omics data within individual cells, expanding our understanding across a broader spectrum of dimensions. Single-cell multi-omics precisely captures the multidimensional aspects of single-cell transcriptomes, immune repertoire, spatial information, temporal information, epitopes, and other omics in diverse spatiotemporal contexts. In addition to depicting the cell atlas of normal or diseased tissues, it also provides a cornerstone for studying cell differentiation and development patterns, disease heterogeneity, drug resistance mechanisms, and treatment strategies. Herein, we review traditional single-cell sequencing technologies and outline the latest advancements in single-cell multi-omics. We summarize the current status and challenges of applying single-cell multi-omics technologies to biological research and clinical applications. Finally, we discuss the limitations and challenges of single-cell multi-omics and potential strategies to address them.

Survivin (encoded by the gene BIRC5) plays an important role in the carcinogenesis of bladder cancer. Identifying miRNAs that target Survivin in the setting of bladder cancer will help to develop Survivin-based therapies for bladder cancer. The expression levels of miR-138-5p and Survivin protein were measured in 12 resected bladder cancer specimens. The correlation between miR-138-5p and Survivin was further examined by evaluating Survivin expression in human bladder cancer cell lines that either overexpressed or knocked down miR-138-5p. A luciferase reporter assay was performed to test the direct binding of miR-138-5p to the target gene BIRC5. We also investigated the biological role of miR-138-5p targeting to Survivin in bladder cancer cell lines both in vivo and in vitro. In this study, we found that the Survivin protein was either absent or weakly expressed in normal adjacent tissues and consistently up-regulated in bladder cancer tissues; however, the mRNA levels did not vary as much, suggesting that a post-transcriptional mechanism was involved. Because microRNAs are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for microRNAs that could potentially target BIRC5 in the setting of bladder cancer. We identified 2 specific targeting sites for miR-138-5p in the 3′ untranslated region (3′-UTR) of BIRC5. We further identified an inverse correlation between miR-138-5p and Survivin protein levels in bladder cancer tissue samples. By overexpressing or knocking down miR-138-5p in bladder cancer cells, we experimentally confirmed that miR-138-5p directly recognizes the 3′-UTR of the BIRC5 transcript and regulates Survivin expression. Furthermore, the biological consequences of the targeting of BIRC5 by miR-138-5p were examined in vitro via cell proliferation and invasion assays and in vivo using a mouse xenograft tumor model. We demonstrated that BIRC5 repression by miR-138-5p suppressed the proliferative and invasive characteristics of bladder cancer cells and that miR-138-5p exerted an anti-tumor effect by negatively regulating BIRC5 in a xenograft mouse model. Taken together, our findings provide the first clues regarding the role of miR-138-5p as a tumor suppressor in bladder cancer by inhibiting BIRC5 translation.

Ferroptosis is an iron-dependent form of regulated cell death driven by the lethal lipid peroxides. Previous studies have demonstrated that inducing ferroptosis holds great potential in cancer therapy, especially for patients with traditional therapy failure. However, cancer cells can acquire ferroptosis evasion during progression. To date, the therapeutic potential of inducing ferroptosis in bladder cancer (BCa) remains unclear, and whether a ferroptosis escape mechanism exists in BCa needs further investigation. This study verified that low pathological stage BCa cells were highly sensitive to RSL3-induced ferroptosis, whereas high pathological stage BCa cells exhibited obviously ferroptosis resistance. RNA-seq, RNAi-mediated loss-of-function, and CRISPR/Cas9 experiments demonstrated that ALOX5 deficiency was the crucial factor of BCa resistance to ferroptosis in vitro and in vivo. Mechanistically, we found that ALOX5 deficiency was regulated by EGR1 at the transcriptional level. Clinically, ALOX5 expression was decreased in BCa tissues, and its low expression was associated with poor survival. Collectively, this study uncovers a novel mechanism for BCa ferroptosis escape and proposes that ALOX5 may be a valuable therapeutic target and prognostic biomarker in BCa treatment.

Objectives: Exosomes are essential mediators of intercellular communication as they transport proteins and RNAs between cells. Owing to their tumor‐targeting capacity, immune compatibility, low toxicity, and long half‐life, mesenchymal stem cell‐derived exosomes have great potential for the development of novel antitumor strategies. In this context, the role of exosomes produced by adipose‐derived mesenchymal stem cells (ADSCs) for the treatment of bladder cancer (BC) remains unclear. Here, we investigated the use of ADSCs as a source of therapeutic exosomes, as well as their efficacy in delivering the tumor suppressor miR‐138‐5p in BC.Methods: ADSCs stably expressing miR‐138‐5p were established using Lentivirus infection, and ADSC‐derived miR‐138‐5p exosomes (Exo‐miR‐138‐5p) were isolated from the cell culture medium. The effect of Exo‐miR‐138‐5p on BC cell migration, invasion, and proliferation was evaluated in vitro using wound healing, transwell invasion, and proliferation assays. The in vivo effect of Exo‐miR‐138‐5p was investigated using a subcutaneous xenograft mouse model.Results: Exo‐miR‐138‐5p prevented the migration, invasion, and proliferation of BC cells in vitro. Moreover, ADSC‐derived exosomes could penetrate tumor tissues and successfully deliver miR‐138‐5p to suppress the growth of xenograft tumors in vivo.Conclusions: The present results reveal that ADSC‐derived exosomes are an effective delivery vehicle for small molecule drugs in vivo, and exosome‐delivered miR‐138‐5p is a promising therapeutic agent for BC treatment.

FucoID is an intercellular proximity labeling technique for studying cell-cell interactions (CCIs) via fucosyltransferase (FT)–meditated fucosyl-biotinylation, which has been applied to probe antigen-specific dendritic cell (DC)–T cell interactions. In this system, bait cells of interest with cell surface–anchored FT are used to capture the interacting prey cells by transferring a biotin-modified substrate to prey cells. Here, we leveraged FucoID to study CCIs directed by different molecular pairs, e.g., programmed cell death protein-1(PD-1)/programmed cell death protein-ligand-1 (PD-L1), and identify unknown or little studied CCIs, e.g., the interaction of DCs and B cells. To expand the application of FucoID to complex systems, we also synthesized site-specific antibody-based FT conjugate, which substantially improves the ability of FucoID to probe molecular signatures of specific CCI when cells of interest (bait cells) cannot be purified, e.g., in clinical samples. Collectively, these studies demonstrate the general applicability of FucoID to study unknown CCIs in complex systems at a molecular resolution.