Immune checkpoint inhibitors have significantly improved advanced bladder cancer care, but resistance remains a significant challenge. Adenosinergic signaling is an immunosuppressive mechanism hindered by tumor cells to escape from immune surveillance and suppress antitumor immune responses. Herein, we investigate whether co-targeting the adenosine pathway can modulate tumor immunity and enhance the efficacy of anti-PD-L1 therapy in an orthotopic murine bladder cancer model. We observed higher expression of the ectonucleotidases CD39 and CD73 in tumor cells and CD4+ and CD8+ T cells within the tumor microenvironment and peripheral circulation and upregulation of the adenosine receptors A2A and A2B in tumor cells, further confirming the activation of the adenosinergic pathway in this murine model. CD39 inhibition demonstrated no therapeutic benefits nor synergistic effect with anti-PD-L1 immunotherapy in tumor-bearing mice. On the contrary, CD73 inhibition reduced tumor progression and synergized with anti-PD-L1, leading to complete remission in 38 % of cases and a significant reduction in tumor mass in the remainder compared to anti-PD-L1 monotherapy. This combination resulted in favorable systemic immune modulation, including increased circulating CD4+ and CD8+ T cells and a decreased neutrophil-to-lymphocyte ratio. These findings suggest that the adenosinergic pathway limits the efficacy of anti-PD-L1 immunotherapy in invasive bladder cancer. Targeting the CD73 adenosinergic axis may enhance its effectiveness, offering a promising strategy to overcome resistance.

To evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in peripheral blood for assessing the treatment response to chemoimmunotherapy in primary advanced hypopharyngeal squamous cell carcinoma (HPSCC), we retrospectively reviewed the medical records of patients treated with neoadjuvant taxane-platinum (TP) chemotherapy plus an anti-programmed cell death-1 (PD-1) inhibitor at Wuhan Union Hospital from Jan 2020 to Dec 2022. We collected data on absolute neutrophil, lymphocyte, and platelet counts from routine blood tested at baseline and within a week after the first treatment. A total of 35 patients were included in this study. Post-treatment NLR (rs = - 0.445, p = 0.007) and PLR (rs = - 0.475, p = 0.004) demonstrated negative correlations with treatment response assessed by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). NLR and PLR were significantly lower in patients achieving a complete response than those not achieving it (with p values of 0.04 and 0.02 for NLR and PLR, respectively). Among the 27 patients who underwent radical surgery following three cycles of chemoimmunotherapy, a high PLR after the first treatment was negatively correlated with attaining a pathological complete response (pCR) (rs = - 0.424, p = 0.028). For predicting pCR, the receiver operating characteristic (ROC) curve of PLR after the first treatment yielded an area under the curve (AUC) of 0.759 (95% confidence interval [CI]: 0.572-0.946, p = 0.031), with a sensitivity of 77.8% and a specificity of 72.2%. This research underscores the predictive value of the NLR and PLR in appraising not only the treatment response, as gauged by the RECIST 1.1, but also the pathological response to chemoimmunotherapy in patients with HPSCC.

Gastric cancer (GC) with distant metastases has a poor prognosis, and immune checkpoint inhibitors (ICIs) effectively improve the survival time of patients with this disease. This study aimed to identify effective prognostic markers that can predict the treatment effect of ICIs in patients with stage IV GC.

This study included 256 patients with GC with distant metastases who had received treatment with ICIs. A receiver operating characteristic (ROC) curve was used to analyze the predictive ability and optimal cutoff values of immune-inflammatory markers. Kaplan‒Meier survival curves were used to analyze the differences in progression-free survival (PFS) and overall survival (OS) among patients. Cox proportional hazard regression analysis was used to identify independent prognostic factors for PFS and OS.

By comparing the area under the ROC curve (AUC) of immune-inflammatory markers, we selected the preoperative platelet count/(lymphocyte count × prealbumin count) ratio and fibrinogen/albumin ratio to form a combined score (PLPR-FAR score). The ROC curve revealed that when the PLPR-FAR score was used to predict patient PFS and OS, the AUC were 0.614 and 0.672, respectively. The Kaplan‒Meier survival curve revealed that patients with higher PLPR-FAR scores had significantly shorter PFS and OS than those with lower PLPR-FAR scores. Cox proportional hazard regression analysis revealed that the PLPR-FAR score was an independent risk factor for PFS and OS in stage IV GC patients.

The PLPR-FAR score may help identify which patients are more likely to benefit from ICIs treatment, and could serve as a novel and promising prognostic biomarker.

Immunotherapy emerges as a promising approach, marked by recent substantial progress in elucidating how the host immune response impacts tumor development and its sensitivity to various treatments. Immune checkpoint inhibitors have revolutionized cancer therapy by unleashing the power of the immune system to recognize and eradicate tumor cells. Among these, inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have garnered significant attention due to their remarkable clinical efficacy across various malignancies. This review delves into the mechanisms of action, clinical applications, and emerging therapeutic strategies surrounding PD-1/PD-L1 blockade. We explore the intricate interactions between PD-1/PD-L1 and other immune checkpoints, shedding light on combinatorial approaches to enhance treatment outcomes and overcome resistance mechanisms. Furthermore, we discuss the expanding landscape of immune checkpoint inhibitors beyond PD-1/PD-L1, including novel targets such as CTLA-4, LAG-3, TIM-3, and TIGIT. Through a comprehensive analysis of preclinical and clinical studies, we highlight the promise and challenges of immune checkpoint blockade in cancer immunotherapy, paving the way for future advancements in the field.

The authors' previous study found no significant difference in short-term clinical outcomes between patients undergoing robot-assisted esophagectomy (RAE) with or without thoracic duct resection (TDR). However, the impact of RAE-TDR on long-term prognosis remains unclear.

From January 2019 to July 2020, the study prospectively and consecutively enrolled 127 thoracic duct (TD)-preserved and 73 TD-resected patients who underwent standard McKeown RAE surgery. The overall survival (OS) and recurrence-free survival (RFS) were compared between these two groups.

During a median follow-up period of 48.6 months, the 3-year OS rates were 70.6% and 70.9% in the TD-preserved and TD-resected group, and the 3-year RFS rates were 61.9% and 55.5%, respectively. The TD-preserved and TD-resected groups did not differ significantly in local-regional (12.6% vs. 15.1%; p = 0.623), distant (23.6% vs. 28.8%; p = 0.422), or mixed (2.4% vs. 4.1%; p = 0.670) recurrence. However, among the eight (11%) patients with TD lymph node (LN) metastasis in the TD-resected group, six patients experienced recurrences (1 local-regional and 5 distant). The patients who had thoracic duct lymph node (TDLN) metastasis experienced significantly worse RFS than those who did not (p = 0.04). Additionally, TDLN metastasis was significantly associated with advanced nodal stage (cN2-3, 6/8; p = 0.001) and bulky tumors (pT3, 7/8; p = 0.028).

In ESCC, RAE-TDR does not improve recurrence or survival outcomes. However, identification of TDLN metastasis through TDR carries significant prognostic implications considering its strong association with aggressive tumor biology and inferior oncologic outcomes. Therefore, TDR should not be routinely performed, but its selective application for patients with advanced tumors may provide critical staging information to guide tailored postoperative strategies.

Bone metastases represent frequent and severe complications in various cancers, notably impacting prognosis and quality of life. This review article delves into the genetic and epigenetic mechanisms underpinning drug resistance in bone metastases, a key challenge in effective cancer treatment. The development of drug resistance in cancer can manifest as either intrinsic or acquired, with genetic heterogeneity playing a pivotal role. Intrinsic resistance is often due to pre-existing mutations, while acquired resistance evolves through genetic and epigenetic alterations during treatment. These alterations include mutations in driver genes like TP53 and RB1, epigenetic modifications such as DNA methylation and histone changes, and pathway alterations, notably involving RANK-RANKL signaling and the PI3K/AKT/mTOR cascade. Recent studies underline the significance of the tumor microenvironment in fostering drug resistance, with components such as cancer-associated fibroblasts and hypoxia playing crucial roles. The interactions between metastatic cancer cells and the bone microenvironment facilitate survival and the proliferation of drug-resistant clones. This review highlights the necessity of understanding these complex interactions to develop targeted therapies that can overcome resistance and improve treatment outcomes. Current therapeutic strategies and future directions are discussed, emphasizing the integration of genomic profiling and targeted interventions in managing bone metastases. The evolving landscape of genetic research, including the application of next-generation sequencing and CRISPR technology, offers promising avenues for novel and more effective therapeutic strategies. This comprehensive exploration aims to provide insights into the molecular intricacies of drug resistance in bone metastases, paving the way for improved clinical management and patient care.

Interferon-gamma (IFN-γ) is a cytokine produced mainly by immune cells and can affect cancer cells by modulating the activity of multiple signaling pathways, including the canonical Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) cascade. In melanoma, IFN-γ can exert both anticancer effects associated with cell-cycle arrest and cell death induction and protumorigenic activity related to immune evasion leading to melanoma progression. Notably, IFN-γ plays a crucial role in the response of melanoma patients to immunotherapy with immune checkpoint inhibitors (ICIs), which are currently used in the clinic. As these agents target programmed death-1 (PD-1) and its ligand (PD-L1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3), they are designed to restore the antimelanoma immune response. In this respect, IFN-γ produced by cells in the tumor microenvironment in response to ICIs has a beneficial influence on both immune and melanoma cells by increasing antigen presentation, recruiting additional T-cells to the tumor site, and inducing direct antiproliferative effects and apoptosis in melanoma cells. Therefore, IFN-γ itself and IFN-γ-related gene signatures during the response to ICIs can constitute biomarkers or predictors of the clinical outcome of melanoma patients treated with ICIs. However, owing to its multifaceted roles, IFN-γ can also contribute to developing mechanisms associated with the acquisition of resistance to ICIs. These mechanisms can be associated with either decreased IFN-γ levels in the tumor microenvironment or diminished responsiveness to IFN-γ due to changes in the melanoma phenotypes associated with affected activity of other signaling pathways or genetic alterations e.g., in JAK, which restricts the ability of melanoma cells to respond to IFN-γ. In this respect, the influence of IFN-γ on melanoma-specific regulators of the dynamic plasticity of the cell phenotype, including microphthalmia-associated transcription factor (MITF) and nerve growth factor receptor (NGFR)/CD271 can affect the clinical efficacy of ICIs. This review comprehensively discusses the role of IFN-γ in the response of melanoma patients to ICIs with respect to its positive influence and role in IFN-γ-related mechanisms of resistance to ICIs as well as the potential use of predictive markers on the basis of IFN-γ levels and signatures of IFN-γ-dependent genes.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death that has limited treatment options for advanced stages. Although PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for advanced HCC treatment, their effectiveness is often hampered by the immunosuppressive tumor microenvironment (TME), which is due to hypoxia-driven CXCL12/CXCR4 axis activation. In this study, we developed 807-NPs, lipid-coated tannic acid (TA) nanoparticles that encapsulate BPRCX807, a potent CXCR4 antagonist to target HCC. 807-NPs enhance the pharmacokinetics and improve the tumor availability of BPRCX807 without causing systemic toxicity. Our findings show that 807-NPs block the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages and promoting their repolarization toward the antitumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NPs significantly remodeled the immunosuppressive TME by reprogramming tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype and promoting cytotoxic T-cell infiltration into tumors. This led to suppressed primary tumor growth and metastasis, while enhancing the efficacy of cancer immunotherapies, including PD-1 blockade and whole-cancer cell vaccines, by promoting T-cell activation. Our work demonstrates the potential of using nanotechnology to deliver CXCR4 antagonists for cancer immunotherapy.

Liver diseases, including viral hepatitis, alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC), represent a significant threat to global health due to their high mortality rates. The cGAS-STING pathway, a critical part of the innate immune system, plays a crucial role in detecting cytoplasmic DNA and initiating immune responses, including autoimmune inflammation and antitumor immunity. Genomic instability during cancer progression can trigger this pathway by releasing DNA into the cytoplasm. Emerging research indicates that cGAS-STING signaling is intricately involved in maintaining liver homeostasis and contributes to the pathogenesis of various liver diseases. This review outlines the cGAS-STING pathway, with a particular focus on its activation mechanism and its roles in several notable liver conditions. Specifically, we explore the complex interplay of cGAS-STING signaling in viral hepatitis, ALD, MASLD, and HCC, and discuss its potential as a therapeutic target. For example, in HCC, strategies targeting cGAS-STING include using nanomaterials to deliver STING agonists, combining radiofrequency ablation (RFA) with cGAS-STING activation, and leveraging radiotherapy to enhance pathway activation. Furthermore, modulating cGAS-STING activity may offer therapeutic avenues for viral hepatitis and chronic liver diseases like MASLD and ALD, either by boosting antiviral responses or mitigating inflammation. This review highlights the complex role of cGAS-STING signaling in these specific liver diseases and underscores the need for further research to fully realize its therapeutic potential.

Pyroptosis, an excellent form of immunogenic cell death that can effectively activate antitumor immune responses, is attracting considerable interest as a promising approach for cancer immunotherapy. Immunogenic pyroptosis can recruit and stimulate dendritic cells to provoke further activation and tumor infiltration of T cells by releasing danger-associated molecular patterns, thus improving the tumor response to PD-1/PD-L1 checkpoint blockade immunotherapy. Here, we report the discovery of a bifunctional photosensitizer Nile Violet that can simultaneously trigger caspase-3/GSDME-mediated immunogenic pyroptosis and PD-L1 downregulation for cancer photoimmunotherapy. It was shown that this synergistic therapeutic strategy significantly inhibited tumor growth by triggering a systemic antitumor immune response. This work highlights the potential of inducing immunogenic pyroptosis and PD-L1 downregulation for synergistic tumor ablation via a single agent.

Mucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50-60% five-year survival rate in the US. Immune checkpoint inhibitors (ICIs) have shown promising results in prolonging survival in a subset of patients with recurrent or metastatic disease. However, challenges remain, particularly the limited efficacy of PD-1/PD-L1 blockade therapies. PD-L1 protein expression has been shown to be limited in its predictive power for ICI therapies. Emerging evidence shows that intricate characterisation of the tumour microenvironment (TME) is fundamental to understand interacting cells. This study aims to bridge the gap in understanding the tumor microenvironment by identifying distinct spatial patterns of PD-1/PD-L1 interactions and their association with immunotherapy responses in head and neck squamous cell carcinoma (HNSCC).

In this study, we sought to apply a more nuanced approach to understanding cellular interactions by mapping PD-1/PD-L1 interactions across whole-slide HNSCC tissue samples collected prior to ICI therapy. We used a combination of spatial proteomics (Akoya Biosciences) and an in situ proximity ligation assay (isPLA, Navinci Diagnostics) to visualise PD-1/PD-L1 interactions across cell types and cellular neighbourhoods within the tumour TME.

Our findings indicate the existence of isPLA+ PD-1/PD-L1 interactions between macrophages/CD3 T cell-enriched neighbourhoods and tumour cells at the tumour-stroma boundaries in ICI-resistant tumours. The presence of these dense macrophage-tumour layers, which are either absent or dispersed in responders, indicates a barrier that may restrict immune cell infiltration and promote immune escape mechanisms. In contrast, responders had abundant B and T cell aggregates, predominantly around the tumour edges linked to enhanced immune responses to ICI therapy and better clinical outcomes.

This study highlights the utility of isPLA in detecting distinct tumour-immune interactions within the TME, offering new cellular interaction metrics for stratifying and optimising immunotherapy strategies.

The transporter associated with antigen processing (TAP) is a key component of the classical HLA I antigen presentation pathway. Our previous studies have demonstrated that the downregulation of TAP1 contributes to tumor progression and is associated with an increased presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. However, it remains unclear whether the elevation of MDSCs leads to immune cell exhaustion in tumors lacking TAP1. In this study, we established mouse models of tumors with TAP1 deficiency, and we employed PMN-MDSC depletion to investigate their impact on the immune microenvironment within the tumors. We found that MDSC depletion significantly altered the immune-suppressive effects of TAP1-deficient tumor when anti-PD-1 treatment was administered. Targeting PMN-MDSC may be a promising therapeutic strategy for the treatment of tumors with TAP1 deficiency during ICB treatment.

Immunohistochemistry (IHC) was conducted to assess TAP1 expression in mouse melanoma tissues. Ly6G, F4/80, and NKp46 markers were detected in B16 parental and TAP1 knockout tissues, respectively. To enhance anti-tumor immunity, hyperthermia-treated B16F10 WT cell suspension was injected prior to tumor cell introduction. Subsequently, we established B16F10 TAP1 knockout and WT melanoma mouse models. Tumors were collected, and the immune microenvironment was monitored accordingly. Anti-Ly6G antibody was administered to deplete polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Finally, flow cytometry analysis for immune infiltration, quantitative PCR for cytokine levels, and immunofluorescence assays were performed to analyze the immune response.

The level of Ly6G+ cell infiltration was significantly higher in samples exhibiting low TAP1 expression, while no differences were observed in the infiltration of F4/80+ cells or NKp46+ cells. Furthermore, the immune-suppressive effects associated with PMN-MDSCs were reversed following their elimination; this resulted in an increase in CD8+ T cells and a higher ratio of CD8+ T cells to Tregs, while the infiltration of innate immune cells remained unaffected. Functional markers of these immune cells indicated an active anti-tumoral immune response following the removal of PMN-MDSCs. Quantitative PCR analysis indicated elevated levels of TNF-α and IL-6, accompanied by decreased levels of TGF-β in the tumor microenvironment of TAP1.

Our data indicate that myeloid-derived suppressor cells (PMN-MDSCs) play an essential role in creating a tumorigenic immune microenvironment in TAP1 knockout tumors. Therefore, targeting PMN-MDSCs may become a promising therapeutic strategy for the treatment of tumors with TAP1 deficiency during ICB treatment.

Cervical cancer is one of the most prevalent gynecologic malignancies, posing a significant threat to women's health and survival. Despite advancements in early screening and diagnosis, which have led to cervical cancer being termed a "preventable" cancer, treatment options for advanced and recurrent cervical cancer remain limited. Consequently, identifying new therapeutic targets and treatments is crucial for advancing the research and management of cervical cancer. In recent years, targeted therapy and immunotherapy have become focal points in oncology research, offering new avenues and directions for the treatment of cancer. Preclinical studies have demonstrated that targeting BMI1 can inhibit cervical cancer progression, while immunotherapy has advanced to phase III clinical trials, showing promising results. To date, there have been no reports on the combination of BMI1-targeted therapy and immunotherapy in cervical cancer. This review, therefore, elucidates the current state of research and explores the potential and perspectives of combining targeted therapy with immunotherapy for cervical cancer.

Although rare in non-small cell lung cancer (NSCLC), BRAF mutations present considerable therapeutic challenges. While the use of BRAF and MEK inhibitor combinations has significantly improved survival outcomes in patients with BRAF V600E mutations, no targeted therapies are currently available for class II and III mutations, leaving the optimal treatment strategy and prognosis for these patients uncertain. Additionally, despite immunotherapy typically showing limited benefit in patients with other activating genomic alterations, it appears to deliver comparable efficacy in BRAF-mutated NSCLC, emerging as a potentially viable treatment option, particularly in patients with a history of smoking. However, resistance to BRAF pathway inhibitors is inevitable, leading to disease progression, and a well-defined strategy to overcome these resistance mechanisms is lacking. This review aims to explore the critical challenges in the management of BRAF-mutated NSCLC, providing a comprehensive summary of the current evidence and highlighting ongoing clinical trials that aim to address these critical gaps.

Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

Despite the considerable achievements of antibodies targeting PD-1/PD-L1 in cancer immunotherapy, limitations in antitumor immune response and pharmacokinetics hinder their clinical adoption. Small molecules toward PD-L1 degradation signifies an innovative avenue to modulate PD-1/PD-L1 axis. Herein, we unveil a comprehensive engineering involving the development of new PD-L1 degraders based on the berberine (BBR) and palmatine (PMT) bioactive frameworks and explore their translational potential for cancer immunotherapy using a peptide-drug conjugate strategy. Chemical modifications at the O-9 position of PMT dramatically enhance the PD-L1 degradation capacity. Further conjugation of PMT degraders with an anti-PD-L1 peptide featuring disulfide linkers enables efficient GSH-specific prodrug activation, yielding synergistic immunotherapeutic benefits through both external PD-L1 blockade and internal PD-L1 degradation mechanisms. This work elucidates the compelling charm of the discovery and application of PD-L1 degraders, offering solutions to the challenges in advancing cancer immunotherapy in widespread clinics.

Immune checkpoint blockade, which enhances the reactivity of T cells to eliminate cancer cells, has emerged as a potent strategy in cancer therapy. Besides T cells, natural killer (NK) cells also play an indispensable role in tumor surveillance and destruction. NK Group 2 family of receptor A (NKG2A), an emerging co-inhibitory immune checkpoint expressed on both NK cells and T cells, mediates inhibitory signal via interaction with its ligand human leukocyte antigen-E (HLA-E), thereby attenuating the effector and cytotoxic functions of NK cells and T cells. Developing antibodies to block NKG2A, holds promise in restoring the antitumor cytotoxicity of NK cells and T cells. In this review, we delve into the expression and functional significance of NKG2A and HLA-E, elucidating how the NKG2A-HLA-E axis contributes to tumor immune escape via signal transduction mechanisms. Furthermore, we provide an overview of clinical trials investigating NKG2A blockade, either as monotherapy or in combination with other therapeutic antibodies, highlighting the responses of the immune system and the clinical benefits for patients. We pay special attention to additional immune co-signaling molecules that serve as potential targets on both NK cells and T cells, aiming to evoke more robust immune responses against cancer. This review offers an in-depth exploration of the NKG2A-HLA-E pathway as a pivotal checkpoint in the anti-tumor responses, paving the way for new immunotherapeutic strategies to improve cancer patient outcomes.

PD-L1 is an immune checkpoint molecule mediating cancer immune escape, and its expression level in the tumor has been used as a biomarker to predict response to immune checkpoint inhibitor (ICI) therapy. Our previous study reveals that an 11 amino acid-long ANXA1-derived peptide (named A11) binds and degrades the PD-L1 protein in multiple cancers and is a potential peptide for cancer diagnosis and treatment. Near-infrared fluorescence (NIF) optical imaging of tumors offers a noninvasive method for detecting cancer and monitoring therapeutic responses. In this study, an NIF dye Cy5.5 was conjugated with A11 peptide to develop a novel PD-L1-targeted probe for molecular imaging of tumors and monitor the dynamic changes in PD-L1 expression in tumors. In vitro imaging studies showed that intense fluorescence was observed in triple-negative breast cancer MDA-MB-231, nonsmall cell lung cancer H460, and melanoma A375 cells incubated with Cy5.5-A11, and the cellular uptake of Cy5.5-A11 was efficiently inhibited by coincubation with unlabeled A11 or knockdown of cellular PD-L1 by shRNA. In vivo imaging studies showed accumulation of Cy5.5-A11 in the MDA-MB-231, H460, and A375 xenografts with good contrast from 0.5 to 24 h after intravenous injection, indicating that Cy5.5-A11 possesses the strong ability for in vivo tumor imaging. Moreover, the fluorescent signal of A11-Cy5.5 in the xenografts was successfully blocked by coinjection of unlabeled A11 peptide or knockdown of cellular PD-L1 by shRNA, indicating the specificity of Cy5.5-A11 targeting PD-L1 in tumor imaging. Our data demonstrate that Cy5.5-A11 is a novel tool for tumor imaging of PD-L1, which has the potential for detecting cancer and predicting ICI therapeutic responses.

Although immune checkpoint inhibitors (ICIs) have demonstrated significant survival benefits in some patients diagnosed with gastric cancer (GC), existing prognostic markers are not universally applicable to all patients with advanced GC.

To investigate biomarkers that predict prognosis in GC patients treated with ICIs and develop accurate predictive models.

Data from 273 patients diagnosed with GC and distant metastasis, who un-derwent ≥ 1 cycle(s) of ICIs therapy were included in this study. Patients were randomly divided into training and test sets at a ratio of 7:3. Training set data were used to develop the machine learning models, and the test set was used to validate their predictive ability. Shapley additive explanations were used to provide insights into the best model.

Among the 273 patients with GC treated with ICIs in this study, 112 died within 1 year, and 129 progressed within the same timeframe. Five features related to overall survival and 4 related to progression-free survival were identified and used to construct eXtreme Gradient Boosting (XGBoost), logistic regression, and decision tree. After comprehensive evaluation, XGBoost demonstrated good accuracy in predicting overall survival and progression-free survival.

The XGBoost model aided in identifying patients with GC who were more likely to benefit from ICIs therapy. Patient nutritional status may, to some extent, reflect prognosis.

Recurrent breast cancers often develop resistance to standard-of-care therapies. Identifying targetable factors contributing to cancer recurrence remains the rate-limiting step in improving long-term outcomes. In this study, we identify tumor cell-derived osteopontin as an autocrine and paracrine driver of tumor recurrence. Osteopontin promotes tumor cell proliferation, recruits macrophages, and synergizes with IL-4 to further polarize them into a pro-tumorigenic state. Macrophage depletion and osteopontin inhibition decrease recurrent tumor growth. Furthermore, targeting osteopontin in primary tumor-bearing female mice prevents metastasis, permits T cell infiltration and activation, and improves anti-PD-1 immunotherapy response. Clinically, osteopontin expression is higher in recurrent metastatic tumors versus female patient-matched primary breast tumors. Osteopontin positively correlates with macrophage infiltration, increases with higher tumor grade, and its elevated pathway activity is associated with poor prognosis and long-term recurrence. Our findings suggest clinical implications and an alternative therapeutic strategy based on osteopontin's multiaxial role in breast cancer progression and recurrence.

Microsatellite stability (MSS) colorectal cancer (CRC) has poor sensitivity to immunotherapy and its underlying mechanisms are still unclear. Guanylate binding proteins (GBPs) are a family of GTPase involving innate immune responses by providing defense against invading microbes and pathogens. However, the immunological significances of GBPs in MSS CRC remain unknown.

We utilized bioinformatic tools to comprehensively analysis the expression pattern, clinical relevance, prognostic value, biological function, and immunoregulation effect of distinct GBP members in MSS CRC.

The expression of all seven GBPs in MSS samples are remarkably decreased compared to microsatellite instability-high (MSI-H) samples. Among them, GBP1/2/4/5 are obviously correlated with distant metastasis status. High expression of GBP1/4/5/6 was remarkably related to favorable overall survival (OS) and progression-free survival (PFS) in CRC patients with MSS tumor. Subsequent enrichment analysis revealed that Interferon-gamma (IFN-γ) and NOD-like receptor signaling are the most relevant functions. Besides, the expression patterns of GBPs are remarkably associated with several tumor infiltrated immune cells (e.g. regulatory T cells, CD4+ T cells, and macrophages) and diverse immunoregulatory molecules (e.g. immune checkpoint biomarkers (ICBs) and major histocompatibility complex (MHC) molecules). Moreover, high GBP1/2/4/5 expression predicted better immunotherapy responsiveness in immunotherapy cohorts.

These findings might provide novel insights for the identification of therapeutic targets and potential prognostic biomarkers of GBP family in CRC with MSS samples.

Compared with conventional chemotherapy and targeted therapy, immunotherapy has improved the treatment outlook for a variety of solid tumors, including lung cancer, colorectal cancer (CRC), and melanoma. However, it is effective only in certain patients, necessitating the search for alternative strategies to targeted immunotherapy. The deubiquitinating enzyme USP18 is known to play an important role in various aspects of the immune response, but its role in tumor immunity in CRC remains unclear.

In this study, multiple online datasets were used to systematically analyze the expression, prognosis, and immunomodulatory role of USP18 in CRC. The effect of USP18 on CRC was assessed via shRNA-mediated knockdown of USP18 expression in combination with CCK-8 and colony formation assays. Finally, molecular docking analysis of USP18/ISG15 and programmed death-ligand 1 (PD-L1) was performed via HDOCK, and an ELISA was used to verify the potential of USP18 to regulate PD-L1.

Our study revealed that USP18 expression was significantly elevated in CRC patients and closely related to clinicopathological characteristics. The experimental data indicated that silencing USP18 significantly promoted the proliferation and population-dependent growth of CRC cells. In addition, high USP18 expression was positively correlated with the CRC survival rate and closely associated with tumor-infiltrating CD8+ T cells and natural killer (NK) cells. Interestingly, USP18 was correlated with the expression of various chemokines and immune checkpoint genes. The results of molecular docking simulations suggest that USP18 may act as a novel regulator of PD-L1 and that its deficiency may potentiate the antitumor immune response to PD-L1 blockade immunotherapy in CRC.

In summary, USP18 shows great promise for research and clinical application as a potential target for CRC immunotherapy.

Tumor-associated macrophages play an important role in the tumor immune microenvironment, and regulating the function of tumor-associated macrophages has important therapeutic potential in tumor therapy. Mature macrophages could migrate to the tumor microenvironment, influencing multiple factors such as tumor cell proliferation, invasion, metastasis, extracellular matrix remodeling, immune suppression, and drug resistance. As a major component of the tumor microenvironment, tumor-associated macrophages crosstalk with other immune cells. Currently, tumor-associated macrophages have garnered considerable attention in tumor therapy, broadening the spectrum of drug selection to some extent, thereby aiding in mitigating the prevailing clinical drug resistance dilemma. This article summarizes the recent advances in tumor-associated macrophages concerning immunology, drug targeting mechanisms for tumor-associated macrophages treatment, new developments, and existing challenges, offering insights for future therapeutic approaches. In addition, this paper summarized the impact of tumor-associated macrophages on current clinical therapies, discussed the advantages and disadvantages of targeted tumor-associated macrophages therapy compared with existing tumor therapies, and predicted and discussed the future role of targeted tumor-associated macrophages therapy and the issues that need to be focused on.

Testicular germ cell tumor (TGCT) is a type of tumor with relatively lower incidence but being more prevalent in young men. The expression of programmed cell death ligand 1 (PD-L1) serves as a potential biomarker for predicting the survival outcomes of other tumors. Some studies discovered higher prevalence of PD-L1 in TGCT patients who achieved favorable treatment outcomes, while other studies showed lower or absent expression of PD-L1 in TGCT with the better prognosis as well. Therefore, in order to address this controversy and clarify the association between the expression of PD-L1 and pathological features and prognosis of TGCT, this meta-analysis was conducted.

A comprehensive literature search was performed using following search terms: "testis", "testicle", "testicular", "cancer", "carcinoma", "tumor", "neoplasm", "programmed cell death ligand 1", "programmed death ligand 1", "PD-L1", "PDL1", "B7 homolog 1", "B7-H1", "B7H1" and "CD274". Relevant studies were retrieved according to the inclusion criteria from reputable databases including PubMed, Embase, Web of Science, Cochrane Library and China National Knowledge Infrastructure (CNKI). These studies investigated the expression of PD-L1 in both tumor cells and tumor infiltrating immune cells (TIICs) in TGCT. The overall proportion of PD-L1 positivity was assessed using R programming. Pooled hazard ratio (HR) and odds ratio (OR) with corresponding 95% confidence interval (CI) were calculated using Revman software to evaluate the involvement of PD-L1 expression in TGCT. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality assessment of included studies. Sensitivity analysis and publication bias evaluation were subsequently performed.

A total of eight eligible studies compromising 1,589 patients diagnosed with TGCT were finally included in this study. PD-L1 positivity was detected in 31% and 41% of TGCT patients' tumor cells and TIICs, respectively. The pooled data demonstrated a significant association between elevated PD-L1 expression levels in TIICs and a favorable prognosis characterized by the reduced disease progression and relapse events (HR =0.21, 95% CI: 0.13-0.33). Furthermore, PD-L1+ TIICs exhibited higher prevalence rates in seminoma (OR =2.11, 95% CI: 1.57-2.84) and embryonal carcinoma (OR =6.23, 95% CI: 2.42-16.02) patients. Notably, PD-L1 expression in TIICs displayed a tendency to increase in TGCT patients with lower stages or without lymph node metastasis.

PD-L1 expression was observed in choriocarcinoma tumor cells, while yolk sac tumor and teratoma tumor cells exhibited lower or absent expression of PD-L1. Conversely, PD-L1 expression in TIICs was associated with seminoma and embryonal carcinoma, which was more commonly observed in TGCT patients with lower stages and better prognosis, thereby providing a theoretical foundation for the application of immunotherapy in relapsed/refractory TGCT patients.

Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8+ T cell response to PD-1 blockade through carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Moreover, the ADAM10 inhibitor GI254023X, which blocks sTim-3 production, reduces tumor progression in Tim-3 humanized mice and reverses anti-PD-1 resistance in human tumor-infiltrating lymphocytes (TILs). Overall, human sTim-3 holds great predictive and therapeutic potential in onco-immunotherapy.

Endometrial cancer (EC) is one of the most common gynecologic cancers. In recent years, research has focused on the genetic characteristics of the tumors to detail their prognosis and tailor therapy. In the case of EC, genetic mutations have been shown to underlie their formation. It is very important to know the mechanisms of EC formation related to mutations induced by estrogen, among other things. Noncoding RNAs (ncRNAs), composed of nucleotide transcripts with very low protein-coding capacity, are proving to be important. Their expression patterns in many malignancies can inhibit tumor formation and progression. They also regulate protein coding at the epigenetic, transcriptional, and posttranscriptional levels. MicroRNAs (miRNAs), several varieties of which are associated with normal endometrium as well as its tumor, also play a particularly important role in gene expression. MiRNAs and long noncoding RNAs (lncRNAs) affect many pathways in EC tissues and play important roles in cancer development, invasion, and metastasis, as well as resistance to anticancer drugs through mechanisms such as suppression of apoptosis and progression of cancer stem cells. It is also worth noting that miRNAs are highly precise, sensitive, and robust, making them potential markers for diagnosing gynecologic cancers and their progression. Unfortunately, as the incidence of EC increases, treatment becomes challenging and is limited to invasive tools. The prospect of using microRNAs as potential candidates for diagnostic and therapeutic use in EC seems promising. Exosomes are extracellular vesicles that are released from many types of cells, including cancer cells. They contain proteins, DNA, and various types of RNA, such as miRNAs. The noncoding RNA components of exosomes vary widely, depending on the physiology of the tumor tissue and the cells from which they originate. Exosomes contain both DNA and RNA and have communication functions between cells. Exosomal miRNAs mediate communication between EC cells, tumor-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs) and play a key role in tumor cell proliferation and tumor microenvironment formation. Oncogenes carried by tumor exosomes induce malignant transformation of target cells. During the synthesis of exosomes, various factors, such as genetic and proteomic data are upregulated. Thus, they are considered an interesting therapeutic target for the diagnosis and prognosis of endometrial cancer by analyzing biomarkers contained in exosomes. Expression of miRNAs, particularly miR-15a-5p, was elevated in exosomes derived from the plasma of EC patients. This may suggest the important utility of this biomarker in the diagnosis of EC. In recent years, researchers have become interested in the topic of prognostic markers for EC, as there are still too few identified markers to support the limited treatment of endometrial cancer. Further research into the effects of ncRNAs and exosomes on EC may allow for cancer treatment breakthroughs.

The PD1/PD-L1 immune checkpoint blocking is a promising therapy, while immunosuppressive tumor microenvironment (TME) and poor tumor penetration of therapeutic antibodies limit its efficacy. Repolarization of tumor-associated macrophages (TAMs) offers a potential method to ameliorate immunosuppression of TME and further boost T cell antitumor immunity. Herein, hybrid cell membrane biomimetic nanovesicles (hNVs) are developed by fusing M1 macrophage-derived nanovesicles (M1-NVs) and PD1-overexpressed tumor cell-derived nanovesicles (PD1-NVs) to improve cancer immunotherapy. The M1-NVs promote the transformation of M2-like TAMs to M1-like phenotype and further increase the release of pro-inflammatory cytokines, resulting in improved immunosuppressive TME. Concurrently, the PD1-NVs block PD1/PD-L1 pathway, which boosts cancer immunotherapy when combined with M1-NVs. In a breast cancer mouse model, the hNVs efficiently accumulate at the tumor site after intravenous injection and significantly inhibit the tumor growth. Mechanically, the M1 macrophages and CD8+ T lymphocytes in TME increase by twofold after the treatment, indicating effective immune activation. These results suggest the hNVs as a promising strategy to integrate TME improvement with PD1/PD-L1 blockade for cancer immunotherapy.

Tumor microenvironment (TME) heterogeneity is an important factor affecting the treatment response of immune checkpoint inhibitors (ICI). However, the TME heterogeneity of melanoma is still widely characterized.

We downloaded the single-cell sequencing data sets of two melanoma patients from the GEO database, and used the "Scissor" algorithm and the "BayesPrism" algorithm to comprehensively analyze the characteristics of microenvironment cells based on single-cell and bulk RNA-seq data. The prediction model of immunotherapy response was constructed by machine learning and verified in three cohorts of GEO database.

We identified seven cell types. In the Scissor+ subtype cell population, the top three were T cells, B cells and melanoma cells. In the Scissor- subtype, there are more macrophages. By quantifying the characteristics of TME, significant differences in B cells between responders and non-responders were observed. The higher the proportion of B cells, the better the prognosis. At the same time, macrophages in the non-responsive group increased significantly. Finally, nine gene features for predicting ICI response were constructed, and their predictive performance was superior in three external validation groups.

Our study revealed the heterogeneity of melanoma TME and found a new predictive biomarker, which provided theoretical support and new insights for precise immunotherapy of melanoma patients.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and second leading cause of cancer-related deaths worldwide. The heightened mortality associated with HCC is largely attributed to its propensity for metastasis, which cannot be achieved without remodeling or loss of the basement membrane (BM). Despite advancements in targeted therapies and immunotherapies, resistance and limited efficacy in late-stage HCC underscore the urgent need for better therapeutic options and early diagnostic biomarkers. Our study aimed to address these gaps by investigating and evaluating potential biomarkers to improve survival outcomes and treatment efficacy in patients with HCC.

In this study, we collected the transcriptome sequencing, clinical, and mutation data of 424 patients with HCC from The Cancer Genome Atlas (TCGA) and 240 from the International Cancer Genome Consortium (ICGC) databases. We then constructed and validated a prognostic model based on metastasis and basement membrane-related genes (MBRGs) using univariate and multivariate Cox regression analyses. Five immune-related algorithms (CIBERSORT, QUANTISEQ, MCP counter, ssGSEA, and TIMER) were then utilized to examine the immune landscape and activity across high- and low-risk groups. We also analyzed Tumor Mutation Burden (TMB) values, Tumor Immune Dysfunction and Exclusion (TIDE) scores, mutation frequency, and immune checkpoint gene expression to evaluate immune treatment sensitivity. We analyzed integrin subunit alpha 3 (ITGA3) expression in HCC by performing single-cell RNA sequencing (scRNA-seq) analysis using the TISCH 2.0 database. Lastly, wound healing and transwell assays were conducted to elucidate the role of ITGA3 in tumor metastasis.

Patients with HCC were categorized into high- and low-risk groups based on the median values, with higher risk scores indicating worse overall survival. Five immune-related algorithms revealed that the abundance of immune cells, particularly T cells, was greater in the high-risk group than in the low-risk group. The high-risk group also exhibited a higher TMB value, mutation frequency, and immune checkpoint gene expression and a lower tumor TIDE score, suggesting the potential for better immunotherapy outcomes. Additionally, scRNA-seq analysis revealed higher ITGA3 expression in tumor cells compared with normal hepatocytes. Wound healing scratch and transwell cell migration assays revealed that overexpression of the MBRG ITGA3 enhanced migration of HCC HepG2 cells.

This study established a direct molecular correlation between metastasis and BM, encompassing clinical features, tumor microenvironment, and immune response, thereby offering valuable insights for predicting clinical outcomes and immunotherapy responses in HCC.

This study aims to determine the predictive role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) derived radiomic model in tumor immune profiling and immunotherapy for cholangiocarcinoma. To perform radiomic analysis, immune related subgroup clustering was first performed by single sample gene set enrichment analysis (ssGSEA). Second, a total of 806 radiomic features for each phase of DCE-MRI were extracted by utilizing the Python package Pyradiomics. Then, a predictive radiomic signature model was constructed after a three-step features reduction and selection, and receiver operating characteristic (ROC) curve was employed to evaluate the performance of this model. In the end, an independent testing cohort involving cholangiocarcinoma patients with anti-PD-1 Sintilimab treatment after surgery was used to verify the potential application of the established radiomic model in immunotherapy for cholangiocarcinoma. Two distinct immune related subgroups were classified using ssGSEA based on transcriptome sequencing. For radiomic analysis, a total of 10 predictive radiomic features were finally identified to establish a radiomic signature model for immune landscape classification. Regarding to the predictive performance, the mean AUC of ROC curves was 0.80 in the training/validation cohort. For the independent testing cohort, the individual predictive probability by radiomic model and the corresponding immune score derived from ssGSEA was significantly correlated. In conclusion, radiomic signature model based on DCE-MRI was capable of predicting the immune landscape of chalangiocarcinoma. Consequently, a potentially clinical application of this developed radiomic model to guide immunotherapy for cholangiocarcinoma was suggested.

Cuproptosis is copper-induced cell death. Copper metabolism related genes (CMRGs) were demonstrated that used to assess the prognosis out of tumors. In the study, CMRGs were tested for their effect on TME cell infiltration in Ewing's sarcoma (ES).

The GEO and ICGC databases provided the mRNA expression profiles and clinical features for downloading. In the GSE17674 dataset, 22prognostic-related copper metabolism related genes (PR-CMRGs) was identified by using univariate regression analysis. Subsequently, in order to compare the survival rates of groups with high and low expression of these PR-CMRGs,Kaplan-Meier analysis was implemented. Additionally, correlations among them were examined. The study employed functional enrichment analysis to investigate probable underlying pathways, while GSVA was applied to evaluate enriched pathways in the ES (Expression Set). Through an unsupervised clustering algorithm, samples were classified into two clusters, revealing significant differences in survival rates and levels of immune infiltration.

Using Lasso and step regression methods, five genes (TFRC, SORD, SLC11A2, FKBP4, and AANAT) were selected as risk signatures. According to the Kaplan-Meier survival analysis, the high-risk group had considerably lower survival rates than the low-risk group(p=6.013e-09). The area under the curve (AUC) values for the receiver operating characteristic (ROC) curve were 0.876, 0.883, and 0.979 for 1, 3, and 5 years, respectively. The risk model was further validated in additional datasets, namely GSE63155, GSE63156, and the ICGC datasets. To aid in outcome prediction, a nomogram was developed that incorporated risk levels and clinical features. This nomogram's performance was effectively validated through calibration curves.Additionally, the study evaluated the variations in immune infiltration across different risk groups, as well as high-expression and low-expression groups. Importantly, several drugs were identified that displayed sensitivity, offering potential therapeutic options for ES.

The findings above strongly indicate that CMRGs play crucial roles in predicting prognosis and immune status in ES.

Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy.

Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).

The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL's potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.

These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.

Tumor‑associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor‑promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage‑based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM‑targeting therapeutic strategies and discussed the obstacles and perspectives of TAM‑targeting therapies for cancers.

Cancer immunotherapy has rapidly transformed cancer treatment, yet resistance remains a significant hurdle, limiting its efficacy in many patients. Circular RNAs (circRNAs), a novel class of non-coding RNAs, have emerged as pivotal regulators of gene expression and cellular processes. Increasing evidence indicates their involvement in modulating resistance to cancer immunotherapy. Notably, certain circRNAs function as miRNA sponges or interact with proteins, influencing the expression of immune-related genes, including crucial immune checkpoint molecules. This, in turn, shapes the tumor microenvironment and significantly impacts the response to immunotherapy. In this comprehensive review, we explore the evolving role of circRNAs in orchestrating resistance to cancer immunotherapy, with a specific focus on their mechanisms in influencing immune checkpoint gene expression. Additionally, we underscore the potential of circRNAs as promising therapeutic targets to augment the effectiveness of cancer immunotherapy. Understanding the role of circRNAs in cancer immunotherapy resistance could contribute to the development of new therapeutic strategies to overcome resistance and improve patient outcomes.