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ABSTRACT Previous studies have shown that the effectiveness of immune checkpoint blockade in the treatment of ovarian cancer (OC) is poor. A promising small molecule inhibitor targeting phosphatidylinositol 3‐kinase gamma (PI3Kγ) has recently been applied in combination with other drugs for tumor treatment. This study aimed to determine whether a PI3Kγ inhibitor can enhance the antitumor effects of anti‐programmed death‐1/programmed death ligand‐1 (anti‐PD‐1/PD‐L1) therapies in OC and to explore the underlying immunomolecular mechanism involved. Changes in the expression of PI3Kγ, PD‐1, PD‐L1, and tumor‐associated macrophages (TAMs) during the progression of OC were detected in clinical tissue samples. We also constructed a coculture system of OC cells with lymphocytes for in vitro study, and a subcutaneous and intraperitoneal implantation OC mouse model was constructed for in vivo studies. OC is an immunosuppressed tumor with predominant infiltration of M2 throughout the entire disease course. We also found that a PI3Kγ inhibitor combined with anti‐PD‐1 therapy can enhance the antitumor effects of anti‐PD‐1 agents by modulating the PI3Kγ‐AKT‐NF‐κB pathway, reprogramming TAMs, decreasing the number of myeloid‐derived suppressor cells, increasing the number of CD8+ T cells, and increasing the levels of proinflammatory factors; consequently, this approach transforms the tumor immune microenvironment of OC into a more active state. Phosphatidylinositol 3‐kinase gamma (PI3Kγ) inhibitor can sensitize the anti‐programmed death‐1/programmed death ligand‐1 (anti‐PD‐1/PD‐L1) response in ovarian cancer by modulating the PI3Kγ‐AKT‐NF‐κB pathway to remodel tumor immune microenvironment as an activated status, along with downregulating the expression of PD‐L1.

The presence of Fusobacterium nucleatum is associated with an immunosuppressive tumor immune microenvironment (TIM) in primary colorectal cancer (CRC), contributing to tumor progression. Its persistence in CRC liver metastasis tissues raises questions about its role in modulating local and systemic immune responses and influencing recurrence patterns. This retrospective cohort study of 218 patients with CRC liver metastasis investigated the association of F. nucleatum in CRC liver metastasis tissues with systemic inflammation, TIM alterations, and the number of metastatic organs involved in recurrence. Two‐step polymerase chain reaction (PCR), including digital PCR, detected F. nucleatum in 42% (92/218) of fresh‐frozen specimens of CRC liver metastases. Compared with the F. nucleatum‐none group, the F. nucleatum‐high group showed higher C‐reactive protein levels (0.82 vs. 0.22 mg/dL; Ptrend = 0.02), lower numbers of CD8+ cells (33.2 vs. 65.3 cells/mm2; Ptrend = 0.04) and FOXP3+ cells (11.3 vs. 21.7 cells/mm2; Ptrend = 0.01) in the TIM, and a greater number of metastatic organs involved in recurrence (1.6 vs. 1.1; p < 0.001). The presence of F. nucleatum in CRC liver metastasis tissues was associated with increased systemic inflammation, TIM alterations, and a greater number of metastatic organs involved in recurrence. These findings suggest a potential contribution of F. nucleatum to the metastatic propensity of CRC cells and could inform future research to enhance understanding of the interaction between tumor, host, and microbes in the metastatic process. In this retrospective cohort study of 218 patients with colorectal cancer (CRC) liver metastasis, Fusobacterium nucleatum was detected in liver metastasis tissues in 42% of cases and was associated with increased serum C‐reactive protein levels, reduced numbers of CD8+ cells and FOXP3+ cells in tumor tissues, and an increased number of metastatic organs involved in recurrence. F. nucleatum in CRC liver metastasis tissues might influence systemic and local immune responses and diversify the metastatic organs involved.

Background Cervical cancer (CC) remains a significant global health challenge despite advancements in screening, HPV vaccination, and therapeutic strategies. Tumor heterogeneity, driven by epigenetic modifications, affects immune evasion, metastasis, and treatment response. Cancer-associated fibroblasts (CAFs) play a crucial role in CC progression and therapy resistance. Single-cell sequencing offers new insights but remains underutilized in CC research. This study integrates single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and deconvolution analysis to identify key genes and immunotherapy targets. By constructing a prognostic model and exploring the immune microenvironment, we aim to provide novel insights into CC pathogenesis and potential therapeutic strategies. Methods We utilized scRNA-seq, spatial transcriptomics, deconvolution analysis, and pseudotime trajectory mapping to delineate fibroblast subtypes within the tumor immune microenvironment (TIME) of CC. Functional annotations, differential gene expression profiling, cell–cell communication pathways, and transcription factor networks were systematically analyzed. A prognostic model based on bulk RNA-seq data was constructed and validated through survival analysis, with correlations to immune microenvironment characteristics. Functional experiments investigated the role of SDC1, a critical mediator of fibroblast-tumor crosstalk. Additionally, Fibroblast–tumor cell co-culture systems and functional assays were employed to investigate the paracrine role of SDC1. The CAF MYH11⁺ subpopulation was isolated via fluorescence-activated cell sorting (FACS). Multiplex immunofluorescence and immunohistochemical analyses were performed on both cultured cells and human cervical cancer tissue samples to characterize the spatial distribution and dynamic remodeling of MYH11 during stromal reorganization. Results Six distinct fibroblast subtypes were identified, including the C0 MYH11 + fibroblasts, which exhibited unique roles in stemness maintenance, metabolic activity, and immune regulation. Spatial and functional analyses revealed that the C0 subtype is central to tumor-fibroblast interactions, particularly through the MDK-SDC1 signaling axis. The prognostic model incorporating fibroblast-specific markers demonstrated robust predictive power for patient survival outcomes. Additionally, in vitro SDC1 knockdown significantly inhibited CC cell proliferation, migration, and invasion. Fibroblasts show spatially regulated heterogeneity, with activation markers enriched in the tumor zone and MYH11 highest in normal zones, indicating dynamic stromal remodeling. C0 MYH11 + CAF Promotes Tumor Cell Proliferation, Migration, and Inhibits Apoptosis via Soluble SDC1. Conclusion Our results illustrate, in some ways, the possible immunomodulatory and tumor supporting roles of CAFs in CC TIME and highlight the possibility that the MDK-SDC1 pathway is a promising therapeutic target. This study not only promotes a partially new understanding of temporal heterogeneity in CC, but also provides a possible reference base for the development of new biomarkers and immunotherapy approaches to improve clinical outcomes.

Given the dual role of autophagy presenting in tumorigenesis and inhibition, we established an autophagy-related gene prognostic index (ARGPI) with validation to well predict the biochemical recurrence (BCR), metastasis, as well as chemoresistance for patients with prostate cancer (PCa) who underwent radical radiotherapy or prostatectomy. Then, Lasso and COX regression was used to develop the ARGPI. We performed the whole analyses through R packages (version 3.6.3). Secreted phosphoprotein 1 (SPP1), single-minded 2 (SIM2), serine protease inhibitor b5 (SERPINB5), aldehyde dehydrogenase 2 (ALDH2), and acyl-CoA synthetase long-chain 3 (ACSL3) were eventually used to establish the ARGPI score. Patients were divided into two different-risk groups based on the median ARGPI score, high-risk patients with a higher risk of BCR than low-risk patients (hazard ratio [HR]: 5.46, 95% confidence interval [CI]: 3.23-9.24). The risk of metastasis of high-risk patients was higher than low-risk patients (HR: 11.31, 95% CI: 4.89-26.12). In The Cancer Genome Atlas (TCGA) dataset, we observed similar prognostic value of ARGPI in terms of BCR-free survival (HR: 1.79, 95% CI: 1.07-2.99) and metastasis-free survival (HR: 1.80, 95% CI: 1.16-2.78). ARGPI score showed a diagnostic accuracy of 0.703 for drug resistance. Analysis of gene set enrichment analysis (GSEA) indicated that patients in the high-risk group were significantly positively related to interleukin (IL)-18 signaling pathway. Moreover, ARGPI score was significantly related to cancer-related fibroblasts (CAFs; r = 0.36), macrophages (r = 0.28), stromal score (r = 0.38), immune score (r = 0.35), estimate score (r = 0.39), as well as tumor purity (r = −0.39; all P < 0.05). Drug analysis showed that PI-103 was the common sensitive drug and cell line analysis indicated that PC3 was the common cell line of PI-103 and the definitive gene. In conclusion, we found that ARGPI could predict BCR, metastasis, and chemoresistance in PCa patients who underwent radical radiotherapy or prostatectomy.

Background Glioma, particularly glioblastoma (GBM), is a highly aggressive tumor with limited responsiveness to immunotherapy. PANoptosis, a form of programmed cell death merging pyroptosis, apoptosis, and necroptosis, plays an important role in reshaping the tumor microenvironment (TME) and enhancing immunotherapy effectiveness. This study investigates PANoptosis dynamics in glioma and explores the therapeutic potential of its activation, particularly through natural compounds such as cinobufagin. Methods We comprehensively analyzed PANoptosis-related genes (PANoRGs) in multiple glioma cohorts, identifying different PANoptosis patterns and constructing the PANoptosis enrichment score (PANoScore) to evaluate its relationship with patient prognosis and immune activity. Cinobufagin, identified as a PANoptosis activator, was evaluated for its ability to induce PANoptosis and enhance anti-tumor immune responses both in vitro and in vivo GBM models. Results Our findings indicate that high PANoScore gliomas showed increased immune cell infiltration, particularly effector T cells, and enhanced sensitivity to immunotherapies. Cinobufagin effectively induced PANoptosis, leading to increased immunogenic cell death, facilitated tumor-associated microglia/macrophages (TAMs) polarization towards an M1-like phenotype while augmenting CD4+/CD8 + T cell infiltration and activation. Importantly, cinobufagin combined with anti-PD-1 therapy exhibited significant synergistic effects and prolonged survival in GBM models. Conclusions These findings highlight the therapeutic potential of PANoptosis-targeting agents, such as cinobufagin, in combination with immunotherapy, offering a promising approach to convert “cold” tumors into “hot” ones and improving glioma treatment outcomes.

Hepatocellular carcinoma (HCC) remains a critical global health concern, particularly in regions with high endemicity of hepatitis B, hepatitis C, and non-alcoholic fatty liver disease. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a promising therapeutic strategy for advanced HCC. Despite encouraging results, primary and acquired resistance to ICIs continues to pose significant challenges in clinical practice. Recent research has identified tumor-associated macrophages (TAMs) as key contributors to immune evasion and ICI resistance in HCC, primarily through polarization to the M2 phenotype. M2-polarized TAMs secrete a range of immunosuppressive cytokines that inhibit T cell activation and promote tumor progression through processes such as angiogenesis and epithelial-mesenchymal transition. These mechanisms compromise the efficacy of ICIs and facilitate tumor expansion and metastasis. This review summarizes the role of TAM-related signaling pathways in driving immune evasion and ICI resistance in HCC, with particular emphasis on the contribution of TAM surface receptors and chemokines in immune suppression. Additionally, the review highlights emerging insights into TAM metabolic reprogramming and transcriptional regulation, which have been closely linked to ICI resistance. Furthermore, we explore promising therapeutic strategies targeting TAMs and their associated signaling pathways to enhance ICI efficacy in HCC. Integrating these novel approaches could potentially overcome TAM-driven immune evasion and ICI resistance, boosting the efficacy of immunotherapy and improving patient prognosis in HCC.

PurposeNowadays, it is necessary to explore effective biomarkers associated with tumor immune microenvironment (TIME) noninvasively. Here, we investigated whether the metabolic parameter from preoperative 2-[18F]FDG PET/CT could provide information related to TIME in patients with clear cell renal cell carcinoma (ccRCC).MethodsNinety patients with newly diagnosed ccRCC who underwent 2-[18F]FDG PET/CT prior to surgery were retrospectively reviewed. The immunological features included tumor-infiltrating lymphocytes (TILs) density, programmed death-ligand 1 (PD-L1) expression, and tumor immune microenvironment types (TIMTs). TIMTs were classified as TIMT I (positive PD-L1 and high TILs), TIMT II (negative PD-L1 and low TILs), TIMT III (positive PD-L1 and low TILs), and TIMT IV (negative PD-L1 and high TILs). The relationship between maximum standardized uptake value (SUVmax) in the primary lesion from 2-[18F]FDG PET/CT and immunological features was analyzed. Cox proportional hazards analyses were performed to identify the prognostic factors for disease-free survival (DFS) after nephrectomy.ResultsTumors with high TILs infiltration showed remarkable correlation with elevated SUVmax and aggressive clinicopathological characteristics, such as high World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade. PD-L1 expression on tumor cells was positively associated with WHO/ISUP grade and negatively correlated with body mass index (BMI). However, no correlation was observed between SUVmax and PD-L1 expression, regardless of its spatial tissue distribution. SUVmax of TIMT I and IV was higher than that of TIMT II, but there was remarkable difference merely between TIMT II and IV. In multivariate analysis, SUVmax (P = 0.022, HR 3.120, 95% CI 1.175–8.284) and WHO/ISUP grade (P = 0.046, HR 2.613, 95% CI 1.017–6.710) were the significant prognostic factors for DFS. Six cases (16.2%) with normal SUVmax showed disease progression, while 25 cases (71.4%) with elevated SUVmax experienced disease progression. Conversely, the immunological features held no prognostic value.ConclusionsOur findings demonstrated that 2-[18F]FDG PET/CT could provide metabolic information of TIME for ccRCC patients and develop image-guided therapeutic strategies accordingly. Patients with elevated preoperative SUVmax should be seriously considered, and perioperative immunotherapy might be beneficial for them.

Introduction Diffuse Pleural Mesothelioma (DPM) is a rare and incurable cancer. Immune checkpoint inhibitors (ICIs) marked some advances but only for a limited fraction of patients. Improving response prediction to ICIs is currently a clinical need in DPM. Deletion of CDKN2A gene, in chr9p21.3, is one of the most frequent alterations in DPM. As in other settings, deletion of CDKN2A locus has been associated with an immunosuppressive phenotype. Here we investigated the consequences of CDKN2A deletion (CDKN2Adel) on the tridimensional organization and function of immune infiltrate in DPM. Methods A retrospective cohort of 89 DPMs was analyzed and assessed for CDKN2Adel through digital droplet PCR. Immune-profiling was assessed by analyzing 770 immune-related genes by digital profiling. Finally, morphologically resolved, high-dimensional transcriptomic approach was used to reconstruct the spatial architecture of immune-tumor interaction in wild-type and deleted FFPE samples. Results CDKN2Adel was detected in 41.5% of DPMs and was associated with reduced survival ( p  = 0.04). Bulk gene expression identified 373 differentially expressed genes, of which 98.6% were downregulated in CDKN2Adel samples. These genes were enriched in several immune categories, suggesting significant immune deprivation in deleted tumors. Deconvolution analysis confirmed a major depletion of infiltrating immune cells including effector populations. Spatial transcriptomics revealed that this immunosuppressive phenotype was different according to histotype and prominent in the sarcomatoid lesions. Conclusion These data demonstrated that CDKN2Adel deeply affects the spatial organization of immune microenvironment by depleting immune-signaling and reducing or preventing immune infiltration, supporting the potential implementation of this alteration as ICIs predictive biomarker in DPM.

Tumor‐associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)‐1β was among the most abundant cytokines within the in vitro tumor‐macrophage coculture system, and enhanced IL‐1β expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL‐1β mediated immunosuppression during tumor‐TAMs crosstalk. Mechanistically, we demonstrated that IL‐1β significantly boosted programmed death‐ligand 1 (PD‐L1) expression in tumor cells via the activation of the nuclear factor‐κb signaling cascade. Specifically, IL‐1β released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation‐dependent manner. IL‐1β sustained and intensified immunosuppression by promoting C‐C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL‐1β neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti‐PD‐L1 antibody in tumor‐bearing mouse models. Together, this study presents an IL‐1β‐centered immunosuppressive loop between TAMs and tumor cells, highlighting IL‐1β as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade. The pro‐inflammatory cytokine IL‐1β could be triggered and released from macrophages (Mφ) by lactate derived from tumor cells. Interleukin (IL)‐1β, in turn, drove an immune inhibitory phenotype on tumor cells, especially on the increase in programmed death‐ligand 1, by activating the nuclear factor‐κB (NF‐κB) signaling pathway. Thus, tumor‐released lactate and Mφ‐derived IL‐1β mediated the crosstalk loop and caused immunosuppression. Moreover, activated NF‐κB signaling promoted C‐C motif chemokine ligand 2 secretion in tumor cells, leading to further monocyte recruitment and replenishment of the Mφ population, which maintained the malignant feedback loop (Figure 7).

Clear cell renal cell carcinoma (ccRCC) is a neoplastic disease associated with poor prognosis. Localized disease is successfully treated with nephrectomy; however, advanced disease often requires the combined use of immunotherapy and targeted therapy. To the best of our knowledge, there is no validated method to predict immunotherapy response and there is a lack of knowledge regarding the expression kinetics of exhaustion receptors in the early stages of ccRCC. In the present study, immunohistochemistry and flow cytometry were performed to evaluate the expression levels of five biomarkers associated with immune dysfunction [programmed cell death protein-1 (PD-1), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain containing-3 (TIM-3), cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed death ligand-1 (PD-L1)] in 20 patients diagnosed with localized ccRCC. Immunohistochemistry demonstrated that ccRCC tissue was highly positive for CD3, with low expression of PD-L1 and CTLA-4. Based on flow cytometry, the infiltrating leukocytes were mostly CD8+ lymphocytes and monocytes. In tumors, decreased expression levels of LAG-3, TIM-3, CTLA-4 and PD-L1 were reported; however, expression levels of PD-1 remained unchanged. Sample stratification according to the nuclear grade demonstrated no changes in the evaluated markers. Finally, the 12-month follow-up of blood biomarkers revealed no change in the receptors, except for CTLA-4. The results of the present study suggested that immune exhaustion, defined as increased expression of exhaustion receptors in lymphocytes, was not present in tissues from patients with ccRCC with localized disease.