This study aimed to investigate the safety and efficacy of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) according to different PD-L1 expression statuses in a real-world setting.

This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate.

A total of 409 patients, 65.0% (n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% (n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 109/L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 109/L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs.

A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.

The study investigated the clinicopathological features and characteristic immune tumor microenvironment (TME) of lung squamous cell carcinoma (SqCC) adjacent to emphysematous lesions. 184 consecutive patients with peripheral-type SqCC who had undergone complete surgical resection were enrolled. The clinicopathological differences between emphysema-adjacent SqCC (EA-SqCC) and non-emphysema-adjacent SqCC (non-EA-SqCC) were examined. The immune TME, including tumor-infiltrating lymphocytes (TILs) and PD-L1 expression, was also analyzed. EA-SqCC was detected in 132 (71.7%) of the 184 patients. Patients with EA-SqCC had shorter recurrence-free survival (RFS) [median 58.2 months vs. not Reached (NR); hazard ratio (HR) 0.47; 95% CI 0.25-0.81, p < 0.01] and tended to have shorter overall survival (NR vs. NR; HR 0.47; 95% CI 0.27-1.03, p = 0.07) compared to patients with non-EA-SqCC. Evaluation of TILs in the cancer stroma showed the number of Foxp3+ TILs in the EA-SqCC group was significantly higher than that in the non-EA-SqCC group (median number 58 vs. 43, p < 0.01). However, there were no significant differences in the number of CD8 + T cells and the PD-L1 expression between the two groups. Immunosuppressive microenvironment is a characteristic feature of EA-SqCC, which may contribute to the poor prognosis of this disease.

Polygonati Rhizoma, a traditional Chinese medicine, has demonstrated immunomodulatory and anticancer properties, yet its precise mechanisms in stomach adenocarcinoma (STAD) remain underexplored. This study aims to uncover the multitarget mechanisms of Polygonati Rhizoma in regulating the tumor immune microenvironment in STAD using artificial intelligence (AI)-driven network pharmacology, bioinformatics, and single-cell RNA sequencing, offering new insights into its immunotherapeutic potential. This study harnessed the power of AI to unravel the molecular mechanisms underlying Polygonati Rhizoma's effects. AI-driven methodologies screened 38 putative constituents, retaining 8 based on ADME criteria. Machine Learning algorithms predicted potential targets, which were cross-referenced with 5,569 immune-related genes from GeneCards, revealing 52 immune-associated targets. Differential expression analysis of the STAD data set identified 18 overlapping DEGs with prognostic significance and immune cell infiltration correlations. Key targets (AKT1, TP53, PTGS2 and VEGFA) emerged as central nodes in the network, with AI-assisted molecular docking confirming strong binding affinities, particularly between diosgenin and these core proteins. Molecular dynamics simulations further validated these interactions. Single-cell RNA sequencing revealed distinct target-gene expression patterns across malignant, stromal, and immune cell subsets in digestive-system tumors. In vitro, Polygonati Rhizoma extract significantly inhibited HGC-27 cell viability and increased intracellular ROS levels. These findings underscore the critical role of AI in integrating multiscale analyses, unveiling a multitarget immunomodulatory and antitumor mechanism for Polygonati Rhizoma in STAD, and providing a foundation for future preclinical and clinical studies.

Invasive central nervous system (CNS) cancers are an area where the development of breakthrough therapies is urgently needed. For instance, conditions such as glioblastoma multiforme (GBM) are associated with poor clinical prognosis, with the majority of trials offering no improvement to marginally enhanced survival. Unleashing the potential of targeting the immune system in CNS cancers has gained attention in recent years. Inhibition of immune checkpoints such as CTLA-4, PD-1/PD-L1, TIM-3, and LAG-3 has been attempted in recent trials. While potentially offering a notable edge over other immunotherapies, multi-organ adverse events have been found with the administration of immune checkpoint inhibitors (ICIs). The present review captures the state-of-the-art evidence on ICI treatments in different CNS cancers. Also, we discuss the value of combinational therapies involving ICIs as well as next-generation therapeutics such as bispecific antibodies targeting PD-1/LAG-3/TIM-3 and CRISPR-Cas9-edited PD-1-knock-out checkpoint-resistant CAR T-cells.

Despite the notable success of cancer immunotherapy, its effectiveness is often limited in a significant proportion of patients, highlighting the need to explore alternative tumor immune evasion mechanisms. Adenosine, a key metabolite accumulating in hypoxic tumor regions, has emerged as a promising target in oncology. Inhibiting the adenosinergic pathway not only inhibits tumor progression but also holds potential to enhance immunotherapy outcomes. Multiple therapeutic strategies targeting this pathway are being explored, ranging from preclinical studies to clinical trials. This review examines the complex interactions between adenosine, its receptors, and the tumor microenvironment, proposing strategies to target the adenosinergic axis to boost anti-tumor immunity. It also evaluates early clinical data on pharmacological inhibitors of the adenosinergic pathway and discusses future directions for improving clinical responses.

In recent years, immunotherapy has gradually become one of the main strategies for cancer treatment, with immune checkpoint inhibitors (ICIs) offering new possibilities for tumor therapy. However, some cancer patients exhibit low responses and resistance to ICIs treatment. T cell exhaustion, a process associated with tumor progression, refers to a subset of T cells that progressively lose effector functions and exhibit increased expression of inhibitory receptors. These exhausted T cells are considered key players in the therapeutic efficacy of immune checkpoint inhibitors. Therefore, understanding the impact of T cell exhaustion on tumor immunotherapy and the underlying mechanisms is critical for improving clinical treatment outcomes. Several elegant studies have provided insights into the prognostic value of exhausted T cells in cancers. In this review, we highlight the process of exhausted T cells and its predictive value in various cancers, as well as the relevant mechanisms behind it, providing new insights into the immunotherapy of cancer.

Eliciting a robust immune response against tumors is often hampered by the inadequate presence of effective antigen presenting cells and their suboptimal ability to present antigens within the immunosuppressive tumor microenvironment. Here, we report a cascade antigen relay strategy integrating antigen capturing nanoparticles (AC-NPs) and migratory type 1 conventional dendritic cells (cDC1s), named Antigen Capturing nanoparticle Transformed Dendritic Cell therapy (ACT-DC), to facilitate in situ immunization. AC-NPs are engineered to capture antigens directly from the tumor and facilitate their delivery to adoptively transferred migratory cDC1s, enhancing antigen presentation to the lymph nodes and reshaping the tumor microenvironment. Our findings suggest that ACT-DC improves in situ antigen collection, triggers a robust systemic immune response without the need for exogenous antigens, and transforms the tumor environment into a more "immune-hot" state. In multiple tumor models including colon cancer, melanoma, and glioma, ACT-DC in combination with immune checkpoint inhibitors eliminates primary tumors in 50-100% of treated mice and effectively rejects two separate tumor rechallenges. Collectively, ACT-DC could provide a broadly effective approach for in situ cancer immunization and tumor microenvironment modulation.

Immune checkpoint inhibitors (ICIs) constitute a major breakthrough in the field of cancer therapy; their use has resulted in improved outcomes across various tumour types. However, ICIs can cause a diverse range of immune-related adverse events (irAEs) that present a considerable challenge to the efficacy and safety of these treatments. The gut microbiota has been demonstrated to have a crucial role in modulating the tumour immune microenvironment and thus influences the effectiveness of ICIs. Accumulating evidence indicates that alterations in the composition and function of the gut microbiota are also associated with an increased risk of irAEs, particularly ICI-induced colitis. Indeed, these changes in the gut microbiota can contribute to the pathogenesis of irAEs. In this Review, we first summarize the current clinical challenges posed by irAEs. We then focus on reported correlations between alterations in the gut microbiota and irAEs, especially ICI-induced colitis, and postulate mechanisms by which these microbial changes influence the occurrence of irAEs. Finally, we highlight the potential value of gut microbial changes as biomarkers for predicting irAEs and discuss gut microbial interventions that might serve as new strategies for the management of irAEs, including faecal microbiota transplantation, probiotic, prebiotic and/or postbiotic supplements, and dietary modulations.

Lung cancer continues to be the primary cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all instances. Recently, immune checkpoint inhibitors (ICIs) have transformed the treatment approach for NSCLC, however, only a subset of patients experiences significant benefits. Therefore, identifying reliable biomarkers to forecast the efficacy of ICIs is crucial for ensuring the safety and effectiveness of treatments, becoming a major focus of current research efforts. This review highlights the recent advances in predictive biomarkers for the efficacy of ICIs in the treatment of NSCLC, including PD-L1 expression, tertiary lymphoid structures (TLS), tumor-infiltrating lymphocytes (TILs), tumor genomic alterations, transcriptional signatures, circulating biomarkers, and the microbiome. Furthermore, it underscores the pivotal roles of liquid biopsy, sequencing technologies, and digital pathology in biomarker discovery. Special attention is given to the predictive value of TLS, circulating biomarkers, and transcriptional signatures. The review concludes that the integration of multiple biomarkers holds promise for achieving more accurate efficacy predictions and optimizing personalized immunotherapy strategies. By providing a comprehensive overview of the current progress, this review offers valuable insights into biomarker-based precision medicine for NSCLC and outlines future research directions.

While new intrathoracic adenopathy in a patient with cancer can represent progression of disease, the differential diagnosis is broad. Sarcoid-like reactions (SLR) remain an underreported source of lymphadenopathy in patients treated with immune checkpoint inhibitors (ICI), with limited reports in patients with cancers other than melanoma.

To characterize SLRs among patients treated with ICI for advanced solid tumors.

Data were collected on the clinical, pathologic, and radiographic presentation of patients treated with ICI who developed clinical or imaging findings suggestive of an SLR, including the presence of hilar or mediastinal lymphadenopathy, cutaneous/subcutaneous involvement, and/or worsening of existing sarcoidosis on ICI.

Twelve patients were identified as having experienced an SLR. While 6 patients had melanoma, SLRs were also observed among patients with lung, gynecologic, and genitourinary cancers, including high-grade serous ovarian carcinoma, and an angiomyolipoma. Median time from initiation of ICI to diagnosis of an SLR was 3.4 months (range: 1.8-9.1). All but one patient (92%) were deemed to have had a radiographic response to ICI.

Clinicians should maintain the awareness of the possibility of SLRs in patients receiving ICI, particularly in patients whose scans show evidence of "mixed" response, with decreases in certain lesions coupled with new/increasing intrathoracic lymphadenopathy and/or other systemic signs of sarcoid.

Immune checkpoint inhibitors have revolutionized cancer therapy, but a large proportion of patients do not respond well to current checkpoint immunotherapies. CD200R (also known as OX2R) is a transmembrane glycoprotein of the immunoglobulin superfamily that is mainly expressed on myeloid and lymphoid-derived immunocompetent cells such as myeloid cells, natural killer (NK), and CD8+ T cells. In this study, we investigated the therapeutic potential and cellular mechanisms of targeting CD200R in tumor immunotherapy. We established 4 subcutaneous tumor mouse models using MC38 (colon cancer), MCA205 (fibrosarcoma), LLC (lung cancer), and EO771 (mammary cancer) cell lines. We found that CD200R was highly expressed on tumor-infiltrating NK and CD8+ T cells with exhausted phenotypes in the four subcutaneous tumor mouse models. Either genetic ablation or antibody blockade of CD200R retarded tumor growth and prolonged the survival of tumor-bearing mice by preventing or reversing exhaustion of both NK cells and CD8+ T cells. The combined therapy of CD200R antibody with anti-PD-1/anti-PD-L1 synergistically inhibited tumor growth. By depletion of NK or/and CD8+ T cells, we demonstrated that both cell types contributed to the anti-tumor efficacy of CD200R blockade in tumor-bearing mice. Further, the blockade of human CD200R significantly enhanced human NK cell function and inhibited human tumor growth in PBMC-reconstituted xenograft mice. Our results demonstrate that CD200R is a potential immune checkpoint molecule that can suppress the tumoricidal activities of NK and CD8+ T cells, and could thus be exploited as a therapeutic target in the future.

Cognitive difficulties are frequently reported after cancer treatments, such as chemotherapy or hormone therapy, and have a negative impact on patients' quality of life. Recently, some studies have shown that new cancer treatments, such as immunotherapy agents, can induce cognitive changes.

This review presents the central neurological immune adverse events of immunotherapy treatments including Immune Checkpoint Inhibitors (ICI) and Chimeric Antigen Receptor (CAR) T-cell therapy. The physiopathological mechanisms and risk factors are developed and clinical studies on immunotherapy agents and cognition (among adult patients, using validated questionnaires and/or cognitive tests), psychological factors and quality of life were presented.

Neurological toxicities are frequently observed with CAR-T cell therapies at acute stage, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), inducing cognitive disorders such as disorientation and aphasia. However, few studies have accurately assessed the impact of immunotherapy on cognition. The methodology of these studies is heterogeneous and they mainly included nonspecific self-report questionnaires of cognitive complaints. Variable results have been obtained concerning the cognitive impact of ICI and CAR-T cell several months following immunotherapy: overall, while some studies reported cognitive difficulties (mainly processing speed and executive functions), the majority has not. Although anxiety and depression are frequently reported in patients treated with ICI or CAR-T cells, these symptoms tend to decrease after the start of immunotherapy. The current neurobiological investigations are too fragmentary to explain neurological symptoms and potential cognitive alteration, but neuroinflammation, vascular inflammation, brain blood barrier disruption, and immune cell brain infiltration would constitute common mechanisms relayed by CAR-T and to a lesser degree, ICI.

Acute neurological toxicities following CAR-T cell therapies are a major issue. Further studies are needed to better assess cognitive difficulties after the initiation of immunotherapy, in particular ICI, to better understand the physiopathology, including imaging studies, and risk factors.

Immunotherapy targeting negative immune checkpoint regulators to enhance the anti-tumour immune response holds promise in the treatment of TNBC. V-domain Ig suppressor of T-cell activation (VISTA) is an immune checkpoint molecule, known to be upregulated and involved in modulating tumour immunity in TNBC. However, how VISTA affects immune response and its therapeutic potential in TNBC remains unclear.

Here, we examined VISTA expression and cellular distribution in TNBC patients' samples and pre-clinical TNBC mouse model. Functional assays were performed to assess the impact of VISTA blockade on macrophage phenotypes, CD8 + T cell infiltration and activation, and overall anti-tumour immune response.

In this study we show that VISTA expression levels are increased in TNBC patients' samples and pre-clinical mouse models compared to non-involved breast tissue and VISTA is mainly expressed on tumour infiltrating macrophages and neutrophils. Blocking VISTA reverts macrophages immunosuppressive phenotypes, increases CD8 + T cell infiltration and activation, and enhances an anti-tumour immune response. Mechanistically, we show that neutralising VISTA on macrophages enhances their immune-stimulatory functions and inhibits the suppressive effect of macrophages on CD8 + T cells activation.

These findings provide the rationale for the development of anti-VISTA targeting strategies in the treatment of TNBC.

Immune-related pneumonitis (irP) is a severe immune-related adverse event that can occur after treatment with immune checkpoint inhibitors (ICIs); accurate monitoring and early diagnosis are crucial. Serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are used to diagnose and monitor the disease activity of various types of interstitial lung disease. This study evaluated the usefulness of KL-6 and SP-D for diagnosing irP in cancer patients receiving ICIs.

This retrospective observational study included cancer patients treated with more than two cycles of ICIs from September 2014 to October 2023. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic utility of KL-6 and SP-D.

Of the 724 cancer patients, 631 were included in the analysis, and 64 developed irP. The ROC analysis showed that KL-6 and SP-D had areas under the curve of 0.803 and 0.845, respectively. Serum KL-6 ≥ 500 U/mL had a sensitivity of 65.6% and a specificity of 83.4% for the diagnosis of irP, while SP-D ≥ 110 ng/mL had a sensitivity of 66.7% and a specificity of 88.6%. Combining both KL-6 ≥ 500 U/mL and SP-D ≥ 110 ng/mL resulted in a specificity of 96.6%, with a sensitivity of 46.7%. Combining either KL-6 ≥ 500 U/mL or SP-D ≥ 110 ng/mL resulted in a sensitivity of 85.0%, with a specificity of 75.5%. SP-D levels were significantly associated with irP severity, while KL-6 levels were not.

Serum KL-6 and SP-D are useful for diagnosing irP in cancer patients receiving ICIs.

Nutrient metabolisms are vitally interrelated to cancer progression and immunotherapy. However, the mechanisms by which nutrient metabolisms interact to remodel immune surveillance within the tumor microenvironment remain largely unexplored. Here it is demonstrated that methionine restriction inhibits the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol homeostasis and a potential target for cancer immunotherapy, in colorectal cancer (CRC) but not in the liver. Mechanistically, methionine is catabolized to S-adenosylmethionine (SAM), promoting mRNA transcription of PCSK9 through increased DNA methyltransferase 1 (DNMT1)-mediated DNA methylation and suppression of sirtuin 6 (SIRT6) expression. Furthermore, both PCSK9 inhibition and dietary methionine restriction (DMR) potentiate PD-1 blockade therapy and foster the infiltration of CD8+ T cells in Colon 26 tumor-bearing mice-a proficient mismatch repair (pMMR)/microsatellite stable (MSS) CRC model that exhibits limited response to anti-PD-1 therapy. Moreover, combining 5-fluorouracil (5-FU) chemotherapy with PCSK9 inhibition and PD-1 blockade further augments therapeutic efficacy for MSS CRC. The findings establish a mechanistic link between amino acid metabolism and cholesterol metabolism within the tumor microenvironment where tumor cells sense methionine to regulate PCSK9 expression, highlighting promising combination therapeutic strategies that may greatly benefit MSS CRC patients.

Liver hepatocellular carcinoma (LIHC) is a common cancer with poor prognosis. The FAM72 gene family enhances neuronal self-renewal, potentially increasing tumor formation, but its functional and predictive relevance in LIHC remains unclear. We sought to investigate the function of the FAM72 gene family in LIHC in the present study.

We acquired TCGA-LIHC expression and phenotypic data as well as extensive clinicopathologic information from the UCSC Xena Database (https://xenabrowser.net/datapages/) database. We analyzed the association between FAM72 gene family expression in LIHC and patient prognosis and immune infiltration; Genomic and functional enrichment analysis for FAM72 genes was analyzed. Finally, Western blot method, quantitative real-time polymerase chain reaction and CCK8 detection and cell invasion experiments were used to verify the effect of FAM72A expression on LIHC.

The expression of FAM72 gene family is different between LIHC and normal liver tissues. The expression of FAM72 gene family increased with increasing grading of LIHC tissues. The expression of FAM72 gene family was significantly reduced in LIHC stage IV. LIHC tissues expressed significantly more FAM72 genes than did normal tissues at the T stage (p < 0.001,). which has a good value in the diagnosis of LIHC (AUC greater than 0.85), and was strongly linked with the tumor stage in LIHC. Based on Cox analysis of univariate data, the FAM72 gene family was associated with poor overall survival (OS) in patients with LIHC. Analysis of multifactorial Cox data revealed an independent relationship between FAM72 expression and OS. Increased FAM72 gene expression is associated with poor survival rates and immune cell infiltration. Methylation levels were associated with the prognosis of patients with LIHC. Ultimately, our findings revealed that FAM72A is abundantly expressed in LIHC cells, facilitating proliferation and metastasis.

These findings indicate that the FAM72 gene family is a potential molecular marker for poor prognosis in LIHC, providing additional insights into the development of therapeutic approaches and prognostic markers.

Head and neck squamous cell carcinoma (HNSCC) remains among the most aggressive malignancies with limited treatment options, especially in recurrent and metastatic cases. Despite advances in surgery, radiotherapy, chemotherapy, and immune checkpoint inhibitors, survival rates remain suboptimal due to tumor heterogeneity, immune evasion, and treatment resistance. In recent years, Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized hematologic cancer treatment by genetically modifying T cells to target tumor-specific antigens like CD19, CD70, BCMA, EGFR, and HER2, leading to high remission rates. Its success is attributed to precise antigen recognition, sustained immune response, and long-term immunological memory, though challenges like cytokine release syndrome and antigen loss remain. Notably, its translation to solid tumors, including HNSCC, faces significant challenges, such as tumor microenvironment (TME)-induced immunosuppression, antigen heterogeneity, and limited CAR T-cell infiltration. To address these barriers, several tumor-associated antigens (TAAs), including EGFR, HER2 (ErbB2), B7-H3, CD44v6, CD70, CD98, and MUC1, have been identified as potential CAR T-cell targets in HNSCC. Moreover, innovative approaches, such as dual-targeted CAR T-cells, armored CARs, and CRISPR-engineered modifications, aim to enhance efficacy and overcome resistance. Notably, combination therapies integrating CAR T-cells with immune checkpoint inhibitors (e.g., PD-1/CTLA-4 blockade) and TGF-β-resistant CAR T designs are being explored to improve therapeutic outcomes. This review aimed to elucidate the current landscape of CAR T-cell therapy in HNSCC, by exploring its mechanisms, targeted antigens, challenges, emerging strategies, and future therapeutic potential.

The management of breast cancer, one of the most common and heterogeneous malignancies, has transformed with the advent of precision medicine. This review explores current developments in genetic profiling, molecular diagnostics, and targeted therapies that have revolutionized breast cancer treatment. Key innovations, such as cyclin-dependent kinases 4/6 (CDK4/6) inhibitors, antibody-drug conjugates (ADCs), and immune checkpoint inhibitors (ICIs), have improved outcomes for hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative breast cancer (TNBC) subtypes remarkably. Additionally, emerging treatments, such as PI3K inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and mRNA-based therapies, offer new avenues for targeting specific genetic mutations and improving treatment response, particularly in difficult-to-treat breast cancer subtypes. The integration of liquid biopsy technologies provides a non-invasive approach for real-time monitoring of tumor evolution and treatment response, thus enabling dynamic adjustments to therapy. Molecular imaging and artificial intelligence (AI) are increasingly crucial in enhancing diagnostic precision, personalizing treatment plans, and predicting therapeutic outcomes. As precision medicine continues to evolve, it has the potential to significantly improve survival rates, decrease recurrence, and enhance quality of life for patients with breast cancer. By combining cutting-edge diagnostics, personalized therapies, and emerging treatments, precision medicine can transform breast cancer care by offering more effective, individualized, and less invasive treatment options.

Parabacteroides distasonis (P. distasonis) could regulate inflammatory markers, promote intestinal barrier integrity, and block tumor formation in colon. However, the regulatory effect of P. distasonis on non-small cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the regulatory effect of P. distasonis on NSCLC and its impact on tumor immunity.

We first established a mouse model of Lewis lung cancer, and administered P. distasonis and intrabitoneal injection of anti-mouse PD-1 monoclonal antibody to assess the impact of P. distasonis on tumor immunity, and mouse intestinal barrier. Then, we explored the effect of P. distasonis on CD8+T cells and CXCL9 secretion mediated by tumor-associated macrophages (TAM). We used the TLR1/2 complex inhibitor CPT22 to evaluate its effect on macrophage activation. Finally, we explored the effect of P. distasonis on CD8+T cells and CXCL9 secreted by TAM in vivo.

In vivo, P. distasonis enhanced anti-tumor effects of anti-PD-1 in NSCLC mice, improved intestinal barrier integrity, recruited macrophages, and promoted M1 polarization. In vitro, CD86 and iNOS levels in BMDM were elevated and CD206 and Arg1 levels were suppressed in membrane fraction of P. distasonis (PdMb) group in comparison to Control group. With additional CPT22 pre-treatment, the levels of CD86 and iNOS in BMDM were reduced, and the levels of CD206 and Arg1 were increased. Compared to PBS group, P. distasonis group exhibited higher proportion of CD8+T cells in tumor tissues, along with increased positive proportion of GZMB and IFN-γ in CD8+T cells. Additionally, in comparison to Control group, PdMb group showed an elevated proportion of GZMB+T and IFN-γ+T cells within CD8+T cells, and secretion of IFN-γ, TNF-α, perforin, and GZMB in CD8+T cell supernatant increased. Moreover, the proportion of CXCL9+F4/80+ macrophages in tumor tissues was higher in P. distasonis group compared to PBS group. In comparison to Control group, CXCL9 protein level in BMDM and CXCL9 secretion level in BMDM supernatant were increased in PdMb group. Finally, P. distasonis enhanced CD8+T cell activity by secreting CXCL9 from macrophages in vivo.

P. distasonis promoted CXCL9 secretion of TAM and enhanced CD8+T cell activity to trigger anti-tumor immunity against anti-PD-1 treatment in NSCLC mice.

Immune checkpoint inhibitors (ICIs) improve the outcomes of several types of cancer. However, they are also associated with various immune-related adverse events including myocarditis. ICI-induced myocarditis is a rare, potentially life-threatening adverse event. We herein report two cases of corticosteroid-refractory ICI-induced myocarditis. In both cases, additional immunosuppressive therapies, such as intravenous immunoglobulin and tacrolimus, successfully resolved myocarditis. Given the corticosteroid-refractory nature of these cases, we suggest that prompt addition of other immunosuppressive drugs to corticosteroid therapy should be considered in the treatment of ICI-induced myocarditis.

The treatment of cancer has brought about a paradigm shift with the introduction of immune checkpoint blockade (ICB) therapy, which is mostly dependent on inhibiting PD-1/PD-L1 and CTLA-4. However, recent studies have shown limited efficacy of this treatment in esophageal squamous cell carcinoma (ESCC). Preliminary studies have found that tifcemalimab (the world's first anti-BTLA blocking monoclonal antibody) combined with toripalimab (PD-1) and chemotherapy has shown favorable safety and efficacy in several solid cancers. This study aimed to evaluate the safety and efficacy of neoadjuvant tifcemalimab combined with toripalimab and chemotherapy following esophagectomy for resectable ESCC, and the association of adjuvant immunotherapy with improved survival outcomes.

Patients with pathologically confirmed cT1b-3N1-3M0 or cT2-3N0M0 thoracic ESCC were treated with neoadjuvant tifcemalimab (200mg, iv, d1) in combination with toripalimab (240mg, iv, d1) and chemotherapy (paclitaxel 135-175 mg/m2, d1 + cisplatin 75 mg/m2, d1) every 3 weeks for 2 cycles. Patients undergoing esophagectomy with pathological complete response (pCR) were administered up to 15 cycles of adjuvant tifcemalimab (200 mg) and toripalimab (240 mg), whereas patients without pCR received tifcemalimab in combination with toripalimab and adjuvant chemotherapy for 2 cycles, followed by tifcemalimab in combination with toripalimab immunotherapy up to 13 cycles. The patient with incomplete resection was decided to receive radiotherapy after a multidisciplinary consultation. The primary endpoint of this study was the pCR rate. The secondary endpoints include major pathological response rate (MPR), objective response rate (ORR), disease control rate (DCR), adverse events, R0 resection rate, event-free survival (EFS), and overall survival (OS).

The Ethics Committee of Henan Provincial People's Hospital has approved the protocol (No 2024-132-03). This study is the world's first prospective clinical trial to evaluate the safety and efficacy of the BTLA inhibitor in combination with PD-1 and chemotherapy as neoadjuvant/adjuvant therapy for locally advanced thoracic ESCC. We predicted that perioperative combination immunotherapy as a potentially preferred and effective treatment strategy may lead to better survival outcomes.

Immunotherapy has been at the forefront of cancer treatment research in recent years due to an increased understanding of the immune system's role in cancer and the substantial benefits it has demonstrated compared to conventional treatment methods. In particular, immune cell-based approaches utilizing T cells, natural killer (NK) cells, macrophages, and more have shown great potential as cancer treatments. While these treatments hold promise, there are still numerous issues that limit their clinical translation, including a lack of understanding of their mechanisms and inconsistent responses to treatment. Traditionally, tissue or blood samples are collected as a means of monitoring treatment progression. However, these in vitro diagnostics are invasive and provide limited information about the real-time status of the treatment or its long-term effectiveness. To address these limitations, novel non-invasive imaging modalities have been developed. These include optical imaging, X-ray computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and single-photon emission computed tomography (SPECT), and photoacoustic (PA) imaging. This review focuses on methods for tracking cell-based cancer immunotherapies using these in vivo imaging modalities, thereby enhancing real-time monitoring of their therapeutic effect and predictions of their long-term efficacy.

Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.

The predictive value of the neutrophil-to-lymphocyte ratio (NLR) for immune checkpoint inhibitors (ICIs) in various tumors remains uncertain despite its use in forecasting the effectiveness of immunotherapy. The purpose of our research was to determine the prognostic significance of NLR for immune checkpoint inhibitor-related myocarditis in non-small-cell lung cancer (NSCLC) patients.

We enrolled and monitored patients with NSCLC who received ICI therapy at the Fifth Medical Center of Chinese PLA General Hospital between January 1, 2018, and February 20, 2021. NLR was determined before and soon after each cycle of ICIs. All participants in this study were periodically examined for troponin and brain natriuretic peptide (BNP), and an electrocardiogram (ECG) and echocardiography were done. Cox's proportional hazards regression model and receiver operating characteristic (ROC) were used to assess the predictive value for ICI-related myocarditis.

A total of 146 patients received ICI treatment and completed a follow-up. Of these, 17 patients (11.64%) developed ICI-related myocarditis that met the diagnostic criteria. The initial cycle revealed that the NLR was a reliable predictor of potential myocarditis related to ICIs, with an area under the curve (AUC) of 0.833 and a 95% confidence interval (CI) of 0.721-0.945. Following the initial round of ICI treatment, an NLR elevation (NLR ≥ 3.25) appeared to be the most significant standalone indicator of ICI-related myocarditis (HR: 11.094; 95% CI: 3.186-38.631; p < 0.001).

Our study confirmed that NLR elevation in the early phase after ICI treatment of NSCLC is a reliable predictive factor of ICI-related myocarditis. Regular and frequent cardiac monitoring may help to avoid the occurrence of severe and fatal cases.

Gastrointestinal cancers account for approximately one-fourth of all cancer cases and one-third of all tumor-related deaths worldwide. For the most frequent gastrointestinal tumor entities including colorectal, gastric, esophageal, and liver cancer, the incidence is expected to increase by more than 50% until 2040. While most gastrointestinal cancers are diagnosed beyond the age of fertility and predominantly in men, the increasing incidence of gastrointestinal malignancies in patients below the age of fifty suggests a growing importance in women of childbearing age. While localized cancers in pregnant women can either be monitored or treated surgically, more advanced stages might require radio- or chemotherapy to control tumor growth until delivery. Under these circumstances, critical decisions have to be made to preserve maternal health on the one side and minimize harm to the infant on the other side.

Here we summarize data from case reports, meta-analyses, and registries of women undergoing radio- or chemotherapy during pregnancy and provide guidance for therapeutic decision-making in pregnant women suffering from gastrointestinal cancers.

After the first trimester, most chemotherapeutic regimens can be safely administered to pregnant patients with gastrointestinal cancers. With appropriate safety measures, both radiotherapy and radiochemotherapy can be applied to pregnant patients with rectal cancers.

Immune checkpoint inhibitors (ICI) are the cornerstone of modern oncology; however, side effects such as ICI-related myocarditis (irM) can be fatal. Recently, Bonaca proposed criteria for irM; however, it is unknown if they correlate well with cardiovascular (CV) ICI-related adverse events. Additionally, whether incident irM portends worse long-term CV outcomes remains unclear. We aimed to determine the incidence of long-term CV comorbidities and CV mortality among irM patients.

The ICI-related adverse event (irAE) registry was queried to identify irM patients by using Bonaca criteria. Random controls were selected after excluding patients with other concomitant irAEs. Patients' demographics, comorbidities and myocarditis presenting features were gathered. Outcomes included 2-year freedom from CV comorbidities (composite of atrial fibrillation, stroke, myocardial infarction and heart failure) and freedom from CV death. IrM was treated as a time-varying covariate.

Seventy-six patients developed irM at a median of 167 days (mean age 69, 63.2% male, 47% lung cancer). Majority of patients had new wall motion abnormalities or EKG changes on presentation. Mean LVEF was 43%, median peak TnT was 0.81, and median NTproBNP was 2057 at irM onset. Two-year freedom from CV comorbidities (67% vs 86.8%, P < 0.001) and death (93.4% vs 99.3%, P = 0.003) was lower among irM patients. Incident irM was an independent predictor of CV death (HR 8.28, P = 0.048), but not CV comorbidities (HR 2.21, P = 0.080).

This is the largest case-control study on irM highlighting worse long-term CV outcomes. Future studies are needed to establish appropriate therapeutic strategies and efficient screening strategies for irM survivors.

Oral cavity squamous cell carcinoma (OSCC), a leading subtype of head and neck cancer, exhibits high global incidence and mortality rates. Despite advancements in surgery and radiochemotherapy, approximately one-third of patients experience relapse. To improve current targeted and immunotherapy strategies for recurrent OSCC, we conducted multi-omics analyses on pretreatment OSCC samples (cohorts 1 and 2, n = 137) and identified A3A and EGFR, both at the RNA and protein levels, as inversely expressed markers for patient stratification and response prediction. Survival analysis demonstrated that elevated A3A or PD-L1 expression levels correlated to improved responses to anti-PD-1 therapy in patients (cohort 3a, n = 50, IHC). In contrast, high RRAS expression (cohort 4, n = 252, qRT-PCR) was significantly associated with OSCC recurrence. Cell-based experiments revealed that RRAS was involved in radiotherapy and cisplatin resistance through the EGFR/RRAS/AKT/ERK signaling pathway. In OSCC patient-derived xenograft (PDX) mouse models, treatments with cisplatin and cetuximab (anti-EGFR) effectively reduced tumor size in EGFR-high-derived (#34) but not A3A-high-derived (#22) PDX tumors. Our study demonstrated that A3A-high tumors were immune-hot and responsive to anti-PD-1 therapy, whereas EGFR-high tumors exhibited chr.7p11.2 gains and DNA repair alterations. Additionally, RRAS-high tumors were associated with OSCC recurrence via AKT and ERK phosphorylation and demonstrate improved clinical outcomes with cetuximab therapy (cohort 3b, n = 49, IHC). This study emphasizes the significance of A3A and EGFR expression levels in OSCC patient stratification and precision therapy, suggesting the use of anti-PD-1 or anti-EGFR treatments, respectively based on these biomarkers. Furthermore, RRAS emerges as a novel prognostic marker for local recurrence.

Immune checkpoint inhibitors (ICIs) have revolutionized classical treatment approaches of various cancer entities, but are also associated with a number of side effects. One of these may be life-threatening clotting disorders with the risk of thrombotic or hemorrhagic complications, the mechanisms of which are still poorly understood. In the present study, we analyzed the direct effects of pembrolizumab, nivolumab, and ipilimumab on platelet aggregation as well as plasma coagulation followed by fibrinolysis in an ex vivo model.

Microplate spectrometry was used to analyze aggregation, coagulation, and fibrinolysis in platelet-free (PFP) and platelet-rich (PRP) healthy donor plasma samples treated with pembrolizumab, nivolumab, ipilimumab, and appropriate isotype controls. Aggregation was induced by TRAP-6. Clotting of PFP and PRP followed by lysis was initiated with a tissue factor in a mixture of phosphatidylserine:phosphatidylcholine and the addition of t-PA. Among other parameters, the area under the curve (AUC) was used to compare the effect of ICIs on aggregation, coagulation, and fibrinolysis.

Upon direct contact with platelets, pembrolizumab stimulated platelet aggregation in PRP, while nivolumab and ipilimumab promoted disaggregation with corresponding changes in the AUC. Pembrolizumab and nivolumab, both PD-1 receptor inhibitors, had no effect on the plasma coagulation cascade. Ipilimumab, a CTLA-4 receptor inhibitor, significantly increased the rate of PRP clotting. When clotting was followed by lysis, all ICIs were found to prolong the growth of the PRP-derived fibrin clot and delay its elimination. This was manifested by an increase in AUC relative to control PRP.

This study characterizes the potential impact of pembrolizumab, nivolumab, and ipilimumab on hemostasis. Nivolumab and ipilimumab are able to reduce aggregation and increase the procoagulant properties of platelets, which can cause side effects associated with hemostatic imbalance leading to thrombosis or bleeding. The observed ICI-specific effects may contribute to our understanding of the mechanisms by which ICI affects platelets and suggest how, in a clinical setting, to reduce coagulation disorders during ICI treatment in the future.

Cancer immunotherapy is a well-established therapeutic approach for various types of cancer. However, its clinical utility is usually limited by cardiovascular adverse events. Immune Checkpoint Inhibitors (ICIs) can induce diverse forms of cardiotoxicity, with myocarditis being the most fatal complication. The underlying mechanism of its occurrence remains elusive. Therefore, this study aims to elucidate the impact of programmed death-1 (PD-1) inhibitor on myocarditis development in mice. Myeloid-epithelial-reproductive tyrosine kinase (MerTK) receptors, located on the surface of macrophages, play a pivotal role in phagocytic regulation. We established a mouse model of autoimmune myocarditis by injecting 6-week-old normal male BALB/c mice with PD-1 inhibitor and cardiac troponin I peptide fragments, which resulted in elevated levels of serum soluble MerTK (SolMer) and reduced numbers of MerTK-CD68 double-positive macrophages, accompanied by cardiac injury in mice. In vitro, PD-1 inhibitor promotes a disintegrin and metalloproteinase17 (ADAM17)-mediated shed of the MerTK, forming SolMer, through MKK3/P38 MAPK pathway, leading to downregulation of MerTK expression on the macrophage surface. This results in the inhibition of efferocytosis and impairment of tissue repair function, ultimately contributing to myocarditis development. TAPI-0 inhibited the activity of ADAM17, while SB203580 inhibited the phosphorylation of P38 MAPK. Both inhibitors effectively restored the inhibition of efferocytosis induced by the PD-1 inhibitor. In vitro, when the PD-1 receptor on the surface of RAW264.7 macrophages was knocked down and then stimulated with a PD-1 inhibitor, no further significant alterations in the pathway were elicited. In conclusion, the PD-1 inhibitor induces the shedding of MerTK in macrophages by binding to the PD-1 receptor on the surface of macrophages and activating the MKK3/P38 MAPK/ADAM17 pathway, leading to impaired efferocytosis. Elucidation of this molecular mechanism holds promise for improved prognosis and therapeutic strategies in cancer patients.

This study seeks to investigate the potential synergistic effects of combining ultrasound-guided percutaneous radiofrequency ablation with anti-PD-1 therapy on prostate cancer, utilizing animal models.

A mouse model of prostate cancer was established by subcutaneous injection of 1 × 106 Myc-Cap cells on the right side of FVB mice. When the volume of the tumors reached about 400mm3, the mice were randomly divided into four groups and received corresponding intervention treatments. Among them, Group 1 was the blank control group, Group 2 was the simple anti-PD-1 treatment group, Group 3 was the simple radiofrequency ablation group, and Group 4 is the group that received percutaneous radiofrequency ablation combined with anti-PD-1 therapy under ultrasound guidance. The growth of the tumors was observed in mice after treatment in each group, tumor tissues were collected, and the immune status of the mice was analyzed through flow cytometry, immunohistochemistry, immunofluorescence, and other methods.

Compared with other treatment groups, ultrasound-guided percutaneous radiofrequency ablation combined with anti-PD-1 therapy significantly reduced the weight and volume of the tumors, demonstrating more effective tumor suppression. At the same time, combination therapy can promote the aggregation of T-cells within the tumor and increase the proportion of cytotoxic T-cells, increase the proportion of M1 macrophages and iNOS expression, and decrease the proportion of M2 macrophages and Arg expression in the local area of the tumors.

Local ablation can improve the therapeutic effect of PD-1 monoclonal antibody. Our preliminary results suggest that ultrasound-guided percutaneous radiofrequency ablation, in combination with anti-PD-1 treatment, produces synergistic effects. These effects may be driven by changes in immune cell populations within the tumor's immunosuppressive microenvironment.

Molecular imaging of immune activation holds tremendous potential for the development of novel immunotherapy. In particular, chemical probes capable of detecting immune responses before changes in tumor size occur can guide early therapeutic strategies. Here, we present quenched activity-based probes targeting granzymes as a biomarker of antitumor immunity. Through optimization of peptide recognition element and functional chemical warhead, we have developed an optical imaging probe Cy5-IEPCyaPhP-QSY21, which rapidly reacts with GzmB at substoichiometric concentrations and enables efficient, selective labeling of the active enzyme in a complex proteome. With high specificity and minimal background signal, this probe produces GzmB-induced near-infrared fluorescence signals in the tumors of living mice shortly after injection. Both in vivo and ex vivo fluorescence signals correlate with GzmB expression and activity, and the population of CD8+ cells in tumor tissues. Moreover, it demonstrates the potential to track tumor response to immunotherapy. Thus, this study offers a chemical tool for assessing immune-mediated anticancer activity using noninvasive optical imaging.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment, yet their impact on bone health remains unclear. This study aimed to perform a retrospective cohort study utilizing routine CT scans from patients with melanoma to perform opportunistic QCT analysis to investigate the effects of ICI treatment on skeletal health, including volumetric BMD (vBMD) measurements and osteoarthritis (OA) parameters. A previously established machine learning-assisted opportunistic QCT pipeline was used to estimate lumbar spine vBMD from baseline and 12-mo follow-up CT scans in patients with melanoma treated with ICI therapy and those not treated with ICI therapy. Facet joint OA, osteophyte formation, and endplate sclerosis were also graded. Independent and paired t tests were used to determine any differences in vBMD and OA parameters between ICI users and non-ICI users. Multivariable linear regression models were used to control for confounding variables. Non-ICI users had a significant decrease in vBMD of -6.96 mg/cm3 from baseline to follow-up, whereas the ICI users had no significant change. There was a significant difference in change in vBMD from baseline to follow-up between the 2 groups, with the non-ICI users experiencing a 11.22 mg/cm3 larger decrease in vBMD. After adjusting for baseline age, sex, baseline vBMD, and change in OA parameters, this difference remained significant at -13.04 mg/cm3. Among the ICI users, those who had a decline in vBMD had a lower baseline vBMD compared with those who had increased vBMD. Neither group showed a significant change in OA parameters over the follow-up period, nor a difference in change between ICI and non-ICI users, even after adjusting for sex, age, and baseline OA parameters. While the effects of ICI treatment on vBMD may vary based on baseline bone health, ICIs do not significantly impact OA parameters in the short term.