As one of the key tools of biocatalysis, natural enzymes have received extensive attention due to their unique activity. However, the non-selective catalysis and early leakage induced by delivery dependency of natural enzymes can cause side effects on normal tissues. Moreover, although cuproptosis is an emerging tumor-inhibiting programmed cell death, the occurrence of cuproptosis leads to high expression of Cu-dependent lysyl oxidase-like 2 (LOXL2), which promotes tumor metastasis. Herein, in order to intelligently regulate the "OFF-to-ON" catalytic activity of glucose oxidase (a natural enzyme called GOx) and simultaneously inhibit tumor metastasis caused by Cu imbalance, an acidity-unlocked GOx system drug carrier was constructed by co-assembling Cu ions and omeprazole (OPZ) on GOx exposing sulfhydryl and hydrophobic pockets. The GOx activity is significantly inhibited due to the coordination of Cu ions with sulfhydryl groups and the interaction of hydrophobic small molecule OPZ with hydrophobic bags, which results in specificity for tumor cells and ensures the safety of GOx in blood circulation. Meanwhile, dysregulation of intracellular Cu homeostasis that impairs the Cu-dependence of LOXL2 not only inhibits critical signaling during epithelial-mesenchymal transformation (EMT) and extracellular matrix (ECM) remodelling to prevent tumor metastasis, but also exacerbates enhanced cuproptosis induced by tumor metabolic stress, thereby reversing the immunosuppressive microenvironment. This strategy of acidity-unlocked the catalytic function of natural enzymes and LOXL2 activity inhibition provides a novel option for enhancing cuproptosis to inhibit tumor metastasis and anti-tumor immunity.

Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.

Cancer immunotherapy stimulates and enhances antitumor immune responses to eliminate cancer cells. Neoantigens, which originate from specific mutations within tumor cells, are key targets in cancer immunotherapy. Neoantigens manifest as abnormal peptide fragments or protein segments that are uniquely expressed in tumor cells, making them highly immunogenic. As a result, they activate the immune system, particularly T cell‑mediated immune responses, effectively identifying and eliminating tumor cells. Certain tumor‑associated antigens that are abnormally expressed in normal host proteins in cancer cells are promising targets for immunotherapy. Neoantigens derived from mutated proteins in cancer cells offer true cancer specificity and are often highly immunogenic. Furthermore, most neoantigens are unique to each patient, highlighting the need for personalized treatment strategies. The precise identification and screening of neoantigens are key for improving treatment efficacy and developing individualized therapeutic plans. The neoantigen prediction process involves somatic mutation identification, human leukocyte antigen (HLA) typing, peptide processing and peptide‑HLA binding prediction. The present review summarizes the major current methods used for neoantigen screening, available computational tools and the advantages and limitations of various techniques. Additionally, the present review aimed to summarize experimental strategies for validating the immunogenicity of the predicted neoantigens, which will determine whether these neoantigens can effectively trigger immune responses, as well as challenges encountered during neoantigen screening, providing relevant recommendations for the optimization of neoantigen‑based immunotherapy.

Neutrophils, crucial in the immune system, have recently been implicated in promoting malignancy. RNA methylation, an essential epigenetic feature, plays a key role in tumor microenvironment (TME) reprogramming. However, the relationship between neutrophils and RNA methylation in hepatocellular carcinoma (HCC) remains unclear.

We analyzed single-cell sequencing data from HCC, focusing on cell subtype and TME construction. RNA methylation "writers" were selected, and their expression in neutrophils was evaluated. Two neutrophil subtypes (high/low RNA methylation) were identified. Differentially expressed genes (DEGs) between these subtypes were confirmed, leading to the identification of 6 molecular subtypes via consensus clustering. A prognostic scoring system was developed using LASSO Cox regression, resulting in a novel neutrophil RNA methylation (NRM) scoring system to assess TME heterogeneity and clinical features.

TRPM3, specifically expressed in HCC-infiltrating neutrophils, may regulate RNA modification in tumor pathogenesis. HCC patients were stratified into low/high-NRM score groups, further refined into an advanced NRM (a-NRM) score by incorporating lncRNA data. High a-NRM scores correlated with advanced TNM stage, higher pathological grade, and increased suppressive immune cells. A nomogram incorporating the a-NRM score demonstrated a concordance index indicative of good predictive performance.

The a-NRM score is a reliable predictor of prognosis and could guide treatment selection in HCC patients, enhancing clinical response to immunotherapy. TRPM3 also presents as a potential therapeutic target in HCC.

The composition of the tumor immune microenvironment has become a major determinant of response to therapy, particularly immunotherapy. Clinically, a tumor microenvironment lacking lymphocytes, so-called "cold" tumors, are considered poor candidates for immune checkpoint inhibition. In this review, we describe the diversity of the tumor immune microenvironment in breast cancer and how radiation exposure alters carcinogenesis. We review the development and use of a radiation-genetic mammary chimera model to clarify the mechanism by which radiation acts. Using the chimera model, we demonstrate that systemic inflammation elicited by a low dose of radiation is key to the construction of an immunosuppressive tumor microenvironment, resulting in aggressive, rapidly growing tumors lacking lymphocytes. Our experimental studies inform the non-mutagenic mechanisms by which radiation affects cancer and provide insight into the genesis of cold tumors.

High grade serous ovarian carcinoma (HGSC) is a fatal gynaecological malignancy with limited therapeutic options. Immunotherapies targeting MHC-I-dependent antigen presentation offer potential. Currently, the antigen presentation machinery (APM) of widely used syngeneic murine HGSC models remains poorly characterised, limiting translational relevance. Here, we systematically evaluate APM gene expression in syngeneic murine and patient samples. Tap1 and Psmb8 were identified as critical APM markers, deficient in murine models and strongly correlating with MHC-I expression. Hierarchical clustering correlation analysis using these markers revealed that ID8-p53⁻/⁻BRCA1⁻/⁻ was the most strongly correlated model and aligned with the largest patient subset. Moreover, ID8-ip1 correlated to the smaller second patient subset strongly. The low MHC-I expressing IG10 model was unique clustering alongside patient derived LP28 tumour and not fitting either patient subset. In vivo test of a novel combination immune therapy consisting of Flt3L, Poly(I:C), and paclitaxel therapy demonstrated significantly reduced tumour burden in high APM models (p53⁻/⁻BRCA1⁻/⁻, ID8-ip1; p < 0.01), but not IG10. Furthermore, high expressing MHC-I models were linked to enhanced DC expansion, CD8⁺ T-cell infiltration, and effector differentiation (131 % increase in ID8-ip1), alongside improved CD8⁺ T-cell activation and CD86⁺ B-cell co-stimulation. These findings establish MHC-I as a predictive biomarker for immunotherapy response and underscore the need for APM-enhancing strategies in antigen-poor tumours. By bridging murine models to human APM heterogeneity, this work provides a framework for optimising preclinical immunotherapy evaluation and patient stratification, advancing tailored therapeutic approaches for HGSC.

T-cell receptor T-cell engagers (TCR-TCE) are soluble bispecific proteins composed of TCR and anti-CD3 antibodies, which can effectively redirect tumor-infiltrating T cells to kill tumor cells. However, TCR-TCE development and clinical application are significantly hindered by the instability of natural TCRs and immunosuppressive tumor microenvironment, underscoring the urgent need for alternative engineering strategies. Here, we describe a strategy that utilizes artificial cell membrane nanoparticle technology to generate a TCR nanovesicle antibody (TPC NV), which presents tumor-specific TCR, anti-CD3, and PD-1 antibodies on its membrane, representing a novel TCR-TCE with therapeutic efficacy against solid tumors. TPC NV binds to tumor cells through TCR, redirects tumor-infiltrating T cells via anti-CD3 antibodies, and reverses immunosuppression with anti-PD-1 antibodies, thereby inducing a broad-spectrum T cell response that effectively eliminates established tumors. Furthermore, epacadostat, an inhibitor of indoleamine 2,3-dioxygenase, can be loaded into TPC NV to suppress regulatory T cell (Treg) generation and enhance dendritic cell (DC) maturation by inhibiting tumor tryptophan metabolism. This dual action amplifies adaptive immune activation and triggers a robust systemic anti-tumor immune response.

This multicenter phase Ib/II trial aimed to evaluate the safety and efficacy of combining durvalumab, tremelimumab, and paclitaxel as second-line treatment for biomarker-selected patients with metastatic gastric cancer.

In phase Ib, the standard 3 + 3 dose escalation method was used. Durvalumab and tremelimumab were administered every 4 weeks for 13 and 4 cycles, respectively, combining paclitaxel 80 mg/m2 (dose level 2) or 60 mg/m2 (dose level 1) on days 1, 8, and 15. The primary outcome for phase II was the objective response rate (ORR).

In phase Ib (n = 7), dose level-1 was selected as the recommended phase II dose. In phase II, 48 patients were enrolled: microsatellite instability-high or deficient mismatch repair protein tumors (n = 16); EBV-positive tumors (n = 15); high tumor mutation burden ( ≥ 5/Mb) (n = 11); CD274 amplification (n = 5); and POLD1 mutation (n = 1). The ORR was 52.1%, meeting the primary endpoint. The median progression-free survival and overall survival were 5.3 and 13.1 months, respectively. The most common any-grade and grade 3-4 adverse events were anemia (41.7%) and neutropenia (10.4%), respectively.

Durvalumab-tremelimumab with paclitaxel was tolerable and efficacious in biomarker-selected gastric cancer patients as a second-line treatment, highlighting the importance of biomarker-based approaches for immunotherapy in gastric cancer.

NCT03751761.

Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.

Immune checkpoint inhibitors (ICIs) have revolutionized colon cancer treatment, but their efficacy is largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs). However, the specific genetic alterations that impact the CD8+ CTL infiltration in colon cancer remain poorly understood. Here, we analyzed clinical and multi-omics data from the Memorial Sloan-Kettering Cancer Center (MSKCC) ICIs-treated and The Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) cohorts to screen the key mutations that may influence the efficacy of immunotherapy. We found that patients with NCOA3 mutations exhibit better response to immunotherapy and higher CD8+ CTL infiltration. In vitro and in vivo experiments revealed that mutant NCOA3 increases the efficacy of anti-PD-L1 and CD8+ CTL recruitment by upregulating C-X-C motif chemokine ligand 9 (CXCL9), which is dependent on its impaired intrinsic histone acetyltransferase activity. Mechanistically, wild-type NCOA3 as histone acetyltransferase upregulates Heat shock protein 90 alpha (HSP90α) by enhancing histone H3 lysine 27 acetylation (H3K27ac) at its promoter region. Increased HSP90α stabilizes Enhancer of zeste homolog 2 (EZH2), which then increase the histone H3 lysine 27 trimethylation (H3K27me3) at the CXCL9 promoter region, thereby suppressing the expression of CXCL9. Targeted inhibition of NCOA3 by small molecular inhibitor SI-2 improves the efficacy of PD-L1 blockade therapy. NCOA3 could serve as a novel biomarker and potential target to improve the efficacy of immunotherapy.

Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.

The success of cancer prevention vaccines targeting cancer-causing viruses has drastically reduced cancer mortality worldwide. However, the development of therapeutic cancer vaccines, which aim to elicit an immune response directly against cancer cells, has faced notable clinical setbacks. In this Review, we explore lessons learned from past cancer vaccine trials and how the field has progressed into an era of renewed promise. Previous vaccines primarily targeted tumour-associated antigens and were mainly tested as monotherapies in late-stage cancers. In contrast, contemporary vaccines focus on targeting tumour-specific antigens (neoantigens) and are showing initial evidence of clinical efficacy, particularly in early-stage cancers and precancers when combined with immune checkpoint inhibitors. Advances in tumour profiling and novel vaccine platforms have enhanced vaccine specificity and potency. We discuss recent clinical trials of therapeutic cancer vaccines and outline future directions for the field.

While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.

Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy in the treatment of colorectal cancer (CRC). However, most evidence has come from clinical trials with strict eligibility criteria. Understanding real-world effectiveness and safety of ICIs in CRC is important to guide routine clinical practice across diverse populations.

A systematic review following PRISMA guidelines was conducted to identify observational studies evaluating ICI-based regimens compared to conventional or combination therapies in patients with CRC. Three databases (MEDLINE, Embase, and Scopus) were searched from inception through March 15, 2025. Eligible studies reported at least one efficacy outcome (e.g., progression-free survival [PFS], overall survival [OS], etc.) and/or safety outcome (e.g., adverse events) among real-world populations with CRC treated with ICIs. Study quality was assessed using the Newcastle-Ottawa Scale, and a narrative synthesis was performed to summarize the key findings. Eleven real-world studies met the inclusion criteria, encompassing data from 2,049 patients. In MSI-H/dMMR metastatic CRC, real-world findings aligned with the survival benefits observed in clinical trials, demonstrating improved PFS and OS compared to conventional therapies. For MSS/pMMR metastatic CRC, combining ICIs with other agents (e.g., tyrosine kinase inhibitors or chemotherapy) showed improvements but yielded conflicting results. Overall, the safety profiles were comparable to conventional therapies, with treatment-related adverse events occurring at similar rates. Real-world evidence supports the efficacy of ICI monotherapy in MSI-H/dMMR metastatic CRC and suggests potential benefits of ICI-based combination therapies in MSS/pMMR metastatic CRC. However, most of the data are derived from small, single-center cohorts, which limit their generalizability. Further multi-center studies are needed, especially to assess the efficacy of ICI-based combination therapies in the broader CRC population.

Homologous recombination (HR) and mismatch repair (MMR) act as guardians of the human genome, and defects in HR or MMR are causative in at least a quarter of all malignant tumors. Although these DNA repair-deficient tumors are eligible for effective targeted therapies, fully reliable diagnostic strategies based on functional assay have yet to be established, potentially limiting safe and proper application of the molecular targeted drugs. Here we show that transient transfection of artificial DNA substrates enables ultrarapid detection of HR and MMR. This finding led us to develop a diagnostic strategy that can determine the cellular HR/MMR status within one day without the need for control cells or tissues. Notably, the accuracy of this method allowed the discovery of a pathogenic RAD51D mutation, which was missed by existing companion diagnostic tests. Our methods, termed HR eye and MMR eye, are applicable to frozen tumor tissues and roughly predict the response to therapy. Overall, the findings presented here could pave the way for accurately assessing malignant tumors with functional defects in HR or MMR, a step forward in accelerating precision medicine.

New evidence published in Cell provides insight into the interplay between hypoxia-inducible factor activity and downstream neoantigen production in clear cell renal cell carcinoma (ccRCC). Jiang et al. show that HIF2α regulates expression of immunogenic human endogenous retroelements, with implications for antitumor immunity and immunotherapy responsiveness in ccRCC.

Toll-like receptor 3 (TLR3) is a pattern recognition receptor known to play a crucial role in the immune response to cancer. However, its effect on the efficacy of immunotherapy in lung adenocarcinoma (LUAD) remains unclear. This study aims to investigate the role of TLR3 in LUAD by examining its expression levels, prognostic significance, and impact on immune signaling pathways.

We analyzed the impact of TLR3 expression on the prognosis of lung adenocarcinoma patients using data from the Cancer Genome Atlas (TCGA) database and four additional cohorts (GSE72094, GSE30219, GSE50081 and GSE31210). Functional enrichment analyses were performed to compare molecular features between low and high TLR3 expression groups using gene set variation analysis (GSVA). We also examined the correlation between TLR3 and tumor mutation burden (TMB), immune infiltration, and PD-L1 expression. Further experimental validation was conducted using co-culture systems of LUAD cells and peripheral blood mononuclear cells (PBMCs) with PD1 inhibitors, and Western blot analysis to investigate the involvement of NF-κB signaling.

TLR3 expression was significantly lower in LUAD tissues compared to normal tissues, with high TLR3 expression correlating with better survival outcomes across multiple cohorts. High TLR3 expression was associated with increased TMB and enhanced immune activation. Patients with high TLR3 expression exhibited higher immune checkpoint expression and immune cell infiltration. Experimental results showed that TLR3 agonists increased the susceptibility of LUAD cells to activated PBMCs under PD1 inhibitor therapy, inhibiting cell proliferation, migration, and invasion. Additionally, TLR3 has a strong positive correlation with MHC molecules and upregulated PD-L1 expression. NF-κB was identified as a key regulator of PD-L1 expression, with TLR3 agonists enhancing NF-κB and PD-L1 activity.

TLR3 enhances the anti-tumor immune response in LUAD by modulating NF-κB signaling and PD-L1 expression, making it a promising prognostic biomarker and therapeutic target. This study highlights the potential of TLR3 to improve immunotherapy outcomes, providing a comprehensive analysis of its role in LUAD and paving the way for novel therapeutic strategies targeting TLR3-mediated pathways.

The integrity of the genome is maintained by mismatch repair (MMR) proteins that recognize and repair base mismatches and insertion/deletion errors generated during DNA replication and recombination. A defective MMR system results in genome-wide instability and the progressive accumulation of mutations. Tumors exhibiting deficient MMR (dMMR) and/or high levels of microsatellite instability (termed "microsatellite instability high", or MSI-H) have been shown to possess fundamental differences in clinical, pathological, and molecular characteristics, distinguishing them from their "microsatellite stable" (MSS) counterparts. Molecularly, they are defined by a high mutational burden, genetic instability, and a distinctive immune profile. Their distinct genetic and immunological profiles have made dMMR/MSI-H tumors particularly amenable to treatment with immune checkpoint inhibitors (ICIs). The ongoing development of biomarker-driven therapies and the evaluation of novel combinations of immune-based therapies, with or without the use of conventional cytotoxic treatment regimens, continue to refine treatment strategies with the goals of maximizing therapeutic efficacy and survival outcomes in this distinct patient population. Moreover, the resultant knowledge of the mechanisms by which these features are suspected to render these tumors more responsive, overall, to immunotherapy may provide information regarding the potential optimization of this therapeutic approach in tumors with proficient MMR (pMMR)/MSS tumors.

The PGV001 platform is feasible, safe, and immunogenic. The OpenVax pipeline predicted immunogenic neoantigens in tumors with wide-ranging mutational burdens. Data from this study prompted three additional PGV001 trials, one in newly diagnosed glioblastoma, one in urothelial cancer in combination with an ICI, and another in prostate cancer.

To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumour activity of AMG 404, a fully human IgG1 monoclonal antibody targeting programmed cell death-1, in patients with advanced solid tumours.

First-in-human phase I study comprising eight dose expansion cohorts, including cohorts with microsatellite instability-high (MSI-H) tumours and non-small cell lung cancer with high programmed death-ligand 1 expression (NSCLC/PDL1-H, tumour proportion score ≥50%).

Conducted across 28 global sites.

This study enrolled adult patients with histologically or cytologically confirmed metastatic or locally advanced solid tumours not amenable to curative treatment with surgery or radiation. The inclusion criteria included a life expectancy of >3 months, ≥1 measurable or evaluable lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) V.1.1, an Eastern Cooperative Oncology Group performance status of ≤2 and adequate haematological, renal and hepatic function. Patients with prior treatment with checkpoint inhibitors, primary brain tumour or untreated or symptomatic brain metastases and leptomeningeal disease and history of other malignancy within the past 2 years were excluded.

The planned doses were 240 mg, 480 mg and 1050 mg of AMG 404 administered every 4 weeks (Q4W).

Primary endpoints were dose-limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, changes in vital signs and clinical laboratory tests. Secondary endpoints included PK parameters, incidence of antidrug (AMG 404) antibodies and antitumour activity assessed per modified RECIST V.1.1 (objective response, duration of response, progression-free survival (PFS), disease control and duration of stable disease).

A total of 171 patients were enrolled; 168 were treated. Median (range) follow-up was 36.3 weeks (1.6-137.1). No DLTs were observed. Grade 3 and serious treatment-related adverse events occurred in 16 (9.5%) and 12 (7.1%) patients, respectively. The 480 mg Q4W dose was selected as the recommended phase II dose. AMG 404 serum exposure increased approximately dose proportionally. The objective response rate (80% CI) was 19.6% (15.7-24.1) for the overall population and 36.6% (26.4-47.8) and 30.8% (14.2-‍52.3) for cohorts with MSI-H tumours (n=41) and NSCLC/PDL1-H (n=13), respectively. The overall disease control rate (80% CI) was 54.8% (49.5-59.9). The median (80% CI) PFS was 3.7 (3.5-4.5) months for the overall population and 14.8 (9.0-not estimable) and 4.4 (2.2-9.7) months for cohorts with MSI-H tumours and NSCLC/PDL1-H, respectively.

AMG 404 monotherapy was tolerable at the tested doses, with encouraging antitumour activity observed across tumour types.

NCT03853109.

This study aimed to reveal the gene alteration and tumor mutation burden (TMB) statuses of vulvar and vaginal malignant tumors in Japan.

We investigated the cancer genomic profiling (CGP) data of 79 patients with vulvar and vaginal cancers. These data were obtained from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT).

None of the patients had high microsatellite instability. Although 21.9% of the patients with vulvar and vaginal squamous cell carcinoma (SCC) had high TMB, those with other histological types did not. The top single-nucleotide variants (SNVs) in SCC were TERT, TP53, CDKN2A, KMT2D, and NOTCH1. The frequencies of ATRX and PBRM1 were significantly higher in TMB-high SCC than in non-TMB-high SCC.

SCC of the vulva and vagina is expected to have high TMB, and gene alteration status differed between TMB-high and non-TMB-high groups.

Glioma, the primary cancerous tumor of the central nervous system in adults, has a poor outlook. Immune checkpoint blockade therapy has exhibited notable efficacy against various cancer types. Prior research has suggested that the adenosine A1 receptor (ADORA1) facilitates the proliferation of tumors in cancer. Nevertheless, the precise impact of ADORA1 on glioma progression and its influence on anti-programmed death receptor 1 (PD1) therapy, along with the underlying regulatory mechanisms, remain to be fully elucidated.

Bioinformatics was used to explore the correlation between ADORA1 expression and glioma prognosis. The effects of ADORA1 on glioma and anti-PD1 therapy were investigated in both laboratory settings and living organisms.

The results revealed a significant increase in ADORA1 expression in glioma, which was correlated with poor prognosis. Furthermore, ADORA1 inhibition facilitated glioma apoptosis by augmenting kininogen-1 (KNG1). ADORA1 inhibition enhanced T cell recruitment and increased glioma susceptibility to anti-PD1 therapy.

Our findings indicate that inhibiting ADORA1 can induce apoptosis in glioma cells and increase their sensitivity to anti-PD1 therapy. ADORA1 may serve as a prognostic marker for glioma and a potential target to enhance the effectiveness of anti-PD-1 therapy.

Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis and limited treatment options. We respectively reviewed 38 patients with R/R PCNSL treated with zanubrutinib-based regimens in our center. The overall response rate, complete response rate and disease control rate were 76.3%, 47.4% and 92.1%, respectively. The median progression-free survival (PFS) was 31.0 months, the median overall survival (OS) was not reached. Unitivariate analysis by Cox's proportional hazards model revealed that overall response (vs. no response, HR = 0.18, 95%CI:0.07,0.48, p = 0.001), long duration of zanubrutinib (≥6months vs 2-5 months, HR = 0.20, 95%CI:0.06,0.63, p = 0.006) were independent factors for prolonged PFS. The log-rank analysis indicated a prolongation of PFS among patients exhibiting a higher Tumor mutational burden (TMB, ≥14.75muts/Mb) following zanubrutinib-based treatment (p = 0.016). Our data showed promising efficacy with tolerable safety of zanubrutinib-based therapies in patients with R/R PCNSL. Long duration of zanubrutinib may be associated with prolonged PFS.

Immune checkpoint inhibitors and molecular-targeted therapies have dominated recent cancer treatment. However, these treatments face challenges, such as primary and acquired resistance, indicating that not all patients benefit from them. Therefore, the search for new molecular targets is crucial. In addition, immune checkpoint inhibitors have exhibited racial differences in their effectiveness for certain neoplasms. Hence, understanding the genomic landscape of cancers in various racial groups is important. In Japan, health insurance has covered comprehensive genomic profiling since 2019, and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has accumulated genetic abnormalities along with clinical data of patients with various cancers. These data are crucial for advancing cancer research and drug development. This review discusses the genetic abnormalities of the major skin malignancies including melanoma, cutaneous squamous cell carcinoma (cSCC), and extramammary Paget's disease (EMPD), and proposes potential treatment strategies by comparing C-CAT data analysis with other genetic studies. The C-CAT data have emphasized unique genetic alterations in tumors of the Japanese population, particularly racial differences in tumor mutational burden in cutaneous melanoma and cSCC, indicating the importance of personalized treatment strategies that consider racial differences.

Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)-PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes.

We applied a second-generation in situ proximity ligation assay to detect PD1-PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms.

In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1-PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1-PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1-PD-L1 interactions exhibited additional expression of stromal immune mediators (EOMES, HAVCR1/TIM-1, JAML, FCRL1).

Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.

Suppression of tumor-reactive CD8+ T cells is common within the tumor microenvironment. However, little is known about how tumors systemically affect the overall CD8+ T cell compartment. Here we demonstrate that peripheral blood CD8+ T cells from patients with lung cancer showed altered compositions particularly within CD45RA-CCR7- effector memory subpopulation. Specifically, patients with lung cancer exhibited increased frequency of more differentiated effector memory cells, which are less susceptible to T cell-receptor-induced proliferation. Further analysis using single-cell RNA sequencing revealed that these alterations were correlated with reduced quiescence and increased spontaneous activation at a systemic level, indicative of homeostatic dysregulation of the entire CD8+ T cell population. This phenomenon was found to be correlated with a poor clinical response to immune checkpoint inhibitor therapy across four independent cohorts, consisting of a total of 224 patients with lung cancer. These findings suggest that lung cancers continue to counteract potentially tumor-reactive CD8+ T cells by inducing homeostatic dysregulation of the entire CD8+ T cell compartment systematically.

The expression of PD-L1 on cancer cells facilitates tumor immune escape by binding to PD-1 on T cells, thereby inhibiting T cell activity. However, the role of intracellular PD-L1 signaling in tumor progression remains unclear. In this study, we demonstrate that CK2 induces PD-L1 phosphorylation at Thr-285, which enhances PD-L1 protein stability. This phosphorylation disrupts the interaction between LC3B and PD-L1, inhibiting PD-L1 degradation via autophagy. Furthermore, PD-L1-T285 phosphorylation promotes EGFR binding to PD-L1, leading to activation of EGFR downstream signaling. This activation drives non-small cell lung cancer (NSCLC) cell proliferation, migration, invasion, and tumor growth. Conversely, CK2 depletion or treatment with a CK2 inhibitor reversed these effects. Our findings reveal a novel mechanism by which the CK2/PD-L1/EGFR pathway promotes tumor progression.

Neoadjuvant immunochemotherapy is expected to become the standard treatment mode for locally advanced esophageal squamous cell carcinoma (ESCC). This study aims to analyze the clinical outcomes and long-term survival of neoadjuvant immunochemotherapy for locally advanced ESCC, and explore the feasibility of using major pathological response (MPR) as a surrogate endpoint.

This real-world retrospective study consecutively included eligible patients with stage II-IVA locally advanced ESCC who received neoadjuvant immunochemotherapy and surgery between 2019 and 2022 at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine.

This study collected a total of 166 patients, and ultimately included 126 patients after screening. The objective response rate (ORR) was 69.8% (88/126). The incidence of grade 3-4 adverse events (AEs) was 13.5% (17/126). MPR was observed in 49 (38.9%) patients, and 24 (19.0%) patients achieved a complete pathological response (pCR). The median progression-free survival (PFS) was 31.7 months and the 3-year PFS rate was 56.3%. The median overall survival (OS) was not reached and the 3-year OS rate was 70.6%. The median PFS of the non-MPR group was 25.0 months, with the MPR group not achieved (hazard ratio [HR], 2.503; 95% CI 1.359-4.610; P = 0.0022). The median OS in the non-MPR group was 31.7 months and not reached in the MPR group (HR, 3.607; 95% CI 1.576-8.254; P = 0.0012). MPR is an independent prognostic factor affecting OS (HR, 2.522; 95% CI 1.018-6.401; P = 0.046).

Neoadjuvant immunochemotherapy is safe and effective for locally advanced ESCC, and can result in certain survival benefits. MPR can serve as a surrogate endpoint for predicting long-term OS.

Relatlimab and nivolumab combination therapy shows significant efficacy in treating various types of cancer. Current research on the molecular mechanisms of this treatment is abundant, but in-depth investigations into post-treatment resistance remain notably lacking. In this study, we identify significant enrichment of SRY (sex determining region Y)-box 9 (Sox9)+ tumor cells in resistant samples using single cell RNA sequencing (scRNAseq) in a head and neck squamous cell carcinoma (HNSCC) mouse model. In addition, Sox9 directly regulates the expression of annexin A1 (Anxa1), mediating apoptosis of formyl peptide receptor 1 (Fpr1)+ neutrophils through the Anxa1-Fpr1 axis, which promotes mitochondrial fission, inhibits mitophagy by downregulating BCL2/adenovirus E1B interacting protein 3 (Bnip3) expression and ultimately prevents the accumulation of neutrophils in tumor tissues. The reduction of Fpr1+ neutrophils impairs the infiltration and tumor cell-killing ability of cytotoxic Cd8 T and γδT cells within the tumor microenvironment, thereby leading to the development of resistance to the combination therapy. We further validate these findings using various transgenic mouse models. Overall, this study comprehensively explains the mechanisms underlying resistance to the anti-LAG-3 plus anti-PD-1 combination therapy and identifies potential therapeutic targets to overcome this resistance.

Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell-rich or a noninflamed T cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

This study aimed to establish an immune-glycolysis-related prognostic signature (IGRPS) to predict hepatocellular carcinoma (HCC) outcomes. Additionally, it explored the role of this signature in the tumor immune microenvironment (TIME), glycolytic pathways, and immunotherapy.

We analyzed RNA-seq, single-cell sequencing, and immune- and glycolysis-related gene datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Using weighted gene co-expression network analysis (WGCNA), F-test, and Cox regression, we identified key survival-related immune and glycolytic genes (SRIGRGs) and developed an IGRPS through multivariate Cox regression. The IGRPS's predictive performance was validated in training and validation cohorts using Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, and a prognostic nomogram. Its correlation with TIME and its ability to predict immunotherapy outcomes were also assessed. In vitro experiments were conducted to analyze the expression and function of IGRPS genes in HCC.

Thirteen SRIGRGs were identified for constructing the IGRPS. Patients with low-risk scores had significantly longer survival times. The area under the curve (AUC) for ROC curves was over 0.73 for training and 0.7 for validation cohorts, with C-indices of 0.721 and 0.79, respectively. IGRPS was confirmed as an independent prognostic indicator. Patients in the low-risk group showed better responses to combined anti-CTLA4 and anti-PD-1 therapies. In vitro experiments indicated that PRKAG1 and B3GAT3 were upregulated, enhancing glycolysis and promoting HCC cell proliferation and migration.

The IGRPS, based on immune- and glycolysis-related genes, effectively predicted prognosis and immunotherapy responses in HCC patients.

Immune checkpoint blockade (ICB) therapy has transformed cancer treatment, yet many patients fail to respond. Employing single-cell multiomics, we unveil T cell dynamics influencing ICB response across 480 pan-cancer and 27 normal tissue samples. We identify four immunotherapy response-associated T cells (IRATs) linked to responsiveness or resistance and analyze their pseudotemporal patterns, regulatory mechanisms, and T cell receptor clonal expansion profiles specific to each response. Notably, transforming growth factor β1 (TGF-β1)+ CD4+ and Temra CD8+ T cells negatively correlate with therapy response, in stark contrast to the positive response associated with CXCL13+ CD4+ and CD8+ T cells. Validation with a cohort of 23 colorectal cancer (CRC) samples confirms the significant impact of TGF-β1+ CD4+ and CXCL13+ CD4+ and CD8+ T cells on ICB efficacy. Our study highlights the effectiveness of single-cell multiomics in pinpointing immune markers predictive of immunotherapy outcomes, providing an important resource for crafting targeted immunotherapies for successful ICB treatment across cancers.

Immune checkpoint inhibitor (ICI) plus chemotherapy has become the standard of care for advanced non-small cell lung cancer (NSCLC). Nonetheless, reliable efficacy biomarkers of ICI plus chemotherapy are lacking. In this research, we sought to explore efficacy biomarkers and construct robust prognostic models in NSCLC patients treated with ICI plus chemotherapy.

We retrospectively analyzed 171 patients with advanced NSCLC treated with ICI plus chemotherapy. Clinical characteristics and peripheral blood inflammatory indexes were collected and prognostic models were constructed to explore efficacy and prognosis biomarkers of ICI plus chemotherapy.

In the cohort that received first-line ICI plus chemotherapy, pre-treatment neutrophil-to-lymphocyte ratio (NLR) > 3.3 and fibrinogen (FIB) > 3.196 were associated with worse efficacy and were independent risk factors of progression-free survival (PFS). Compared to programmed cell death ligand 1 (PD-L1), the derived NLR-FIB (NF) score had significantly improved accuracy in predicting efficacy and prognosis. In advanced NSCLC patients with targetable oncogenic driver alterations receiving second- or post-line ICI plus chemotherapy, pre-treatment NLR > 3.53 was associated with worse efficacy and was an independent risk factor of PFS and OS; Tyrosine kinase inhibitor (TKI)-PFS > 12 months were independent risk factors of overall survival (OS). Secondary epidermal growth factor receptor (EGFR)-T790M mutation, platelet-to-lymphocyte ratio (PLR) > 196.81 and albumin (ALB) < 40.25 were associated with worse PFS. Based on NLR and TKI-PFS, an NLR-TKI-PFS (NTP) score was constructed with three OS risk prognosis categories: favorable, intermediate, and poor (corresponding to a median OS of 21, 12, and 5.3 months).

The noninvasive NF score, combining NLR > 3.3 and FIB > 3.196, was superior to PD-L1 estimated from tumor tissue in predicting the efficacy and prognosis of first-line ICI plus chemotherapy in advanced NSCLC patients. The noninvasive NTP score, combining NLR > 3.53 and TKI-PFS > 12 months, is a valuable tool for predicting OS and PFS in advanced NSCLC patients with targetable oncogenic driver alterations receiving second- or post-line ICI combination therapy.

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.

Background/Objectives: Mutations in RAS/RAF are common in colorectal cancer (CRC) and play a pivotal role in guiding treatment selection. With the recent advent of immunotherapy, microsatellite (MSI) status, tumor mutation burden (TMB), and POLE mutations, particularly those leading to high TMB, have gained importance in CRC. This study aimed to examine the clinicopathological characteristics of patients with CRC with POLE mutations. Methods: We identified POLE mutations in patients with colorectal cancer who had available next-generation sequencing (NGS) results from a single institute in Korea. RAS/RAF status, MSI status, and TMB were evaluated, and based on the TMB results, patients with POLE mutations were classified as having either pathogenic or non-pathogenic mutations. After excluding non-Korean patients, we compared the groups based on the presence of pathogenic POLE mutations. Results: Five POLE mutations (A456P, P286R, R1111W, R609W, and V922I) were identified. Only A456P and P286R were associated with an exceptionally high TMB, resulting in two patients (1.1%) being categorized as having pathogenic POLE. The POLE-mutant group showed an extremely high TMB and tended to include younger patients. Among the two pathogenic cases, one showed poor histological differentiation, and the tumors were split between the right and left colons (one in each). Conclusions: CRC with POLE mutations tend to exhibit TMB-high, occur in younger patients, localize to the right colon, and display poor histological differentiation. Given that POLE mutations can serve as indicators for immunotherapy, recognizing these mutations is of clinical importance.

Despite harboring the highest tumor mutational burden of all cancers, basal cell carcinoma (BCC) has low immunogenicity. Here, we demonstrate that BCC's low immunogenicity is associated with epigenomic suppression of antigen presentation machinery reminiscent of its cell of origin. Primary BCC had low T cell infiltrates and low human leukocyte antigen class I (HLA-I) expression compared with cutaneous squamous cell carcinoma (SCC) and normal keratinocytes. Forkhead box C1 (Foxc1), a regulator of quiescence in hair follicle stem cells, was expressed in BCC. Foxc1 bound to promoter of interferon regulatory factor 1 and HLA-I genes, leading to their deacetylation and reduced expression. A histone deacetylase inhibitor, entinostat, overcame Foxc1's effect and upregulated HLA-I in BCC. Topical entinostat plus imiquimod immunotherapy blocked BCC development in mice. Collectively, our findings demonstrate that low BCC immunogenicity is associated with a stem-like quiescent program preserved in the tumor cells, which can be blocked to enable BCC immunotherapy.