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Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types, only a subset of patients shows meaningful clinical responses. In particular, advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy. This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer. Therefore, it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment. Here, we review recent findings that reveal the roles of the genetic alterations, androgen receptor signaling, cancer cell plasticity, and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance. Based on preclinical and clinical observations, a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.

The PD-L1/PD-1 signaling axis is a pivotal regulator of T-cell activity and a key mechanism by which tumors evade immune surveillance. Inhibiting this pathway has resulted in significant anti-tumor responses, establishing immune checkpoint blockade (ICB) as a crucial component of modern cancer therapy. However, many patients with high PD-L1 expression do not respond to PD-1/PD-L1 blockade, underscoring the necessity for a deeper investigation into the mechanisms underlying this resistance. Recent studies have identified DRG2 as a critical modulator of anti-PD-1 therapeutic efficacy. While DRG2 depletion enhances IFN-γ signaling and increases the overall PD-L1 levels, it disrupts the recycling of endosomal PD-L1, resulting in reduced surface expression and impaired PD-1 interaction, ultimately compromising therapeutic outcomes. Furthermore, TRAPPC4, HIP1R, and CMTM6 help stabilize PD-L1 by preventing lysosome degradation. When depleted, these proteins have been shown to boost the body’s immune response against tumors. Research into the complex regulatory mechanisms of PD-L1 suggests that targeting DRG2, TRAPPC4, HIP1R, and CMTM6 could enhance the effectiveness of PD-1/PD-L1 blockade therapies. This strategy could create exciting new possibilities for cancer immunotherapy and improve patient outcomes.

Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional approach, we used doxorubicin (DOX) as an ICD inducer, and poly(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform for controlled release of DOX. The diameter of 138.7 nm of DOX-loaded PLGA nanoparticles (DP-NPs) were stable for 14 days in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Furthermore, DOX was continuously released for 14 days, successfully inducing ICD and reducing cell viability in vitro. Directly injected DP-NPs enabled the remaining of DOX in the tumor site for 14 days. In addition, repeated local treatment of DP-NPs actually lasted long enough to maintain the enhanced antitumor immunity, leading to increased tumor growth inhibition with minimal toxicities. Notably, DP-NPs treated tumor tissues showed significantly increased maturated dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) population, showing enhanced antitumor immune responses. Finally, the therapeutic efficacy of DP-NPs was maximized in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (Ab). Therefore, we expect therapeutic efficacies of cancer CIT can be maximized by the combination of DP-NPs with immune checkpoint blockade (ICB) by achieving proper therapeutic window and continuously inducing ICD, with minimal toxicities.

Background Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested. Case presentation We report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla. Extirpation of a lymph node conglomerate revealed 5 melanoma lymph node metastases. Computed tomography showed a liver metastasis (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c). Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after the first combination therapy he developed progressive erythema, paraesthesia and pain on the fingertips of both hands. Both cold and warmth was not well tolerated by the patient. Complete work-up excluded associated conditions or factors such as haematological disorders, rheumatologic disorders, hypertension, diabetes or smoking. Treatment was initiated with prostacyclin 20 μg twice daily and oral prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after the first applications because the pain increased during infusion. The second course of nivolumab and ipilimumab was administered. About 2 weeks later, the patient presented with increased pain and small subungual necrosis. We treated the patient with oral analgetics and intravenous prednisolone 500 mg in tapering dosage. On digital substraction angiography occlusion of all arteries of the fingers was demonstrated. Further rheologic and anti-melanoma treatments were refused by the patient. About 2 months after the second course of nivolumab and ipilimumab combination therapy several fingers showed severe gangrene which finally led to amputations of end phalanges of several fingers. Histopathology did not reveal evidence for vasculitis or other primary vascular pathologies. During the following 2 months the patient experienced dramatic progress of his metastatic disease and finally died at multi-organ failure. Conclusion Presence of rapidly progressive digital ischemia in an elderly patient with cancer should always raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. In patients treated with immune checkpoint inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been reported so far. However, it is debatable whether immune checkpoint blockade may play a pathogenetic role in the development of PAVS in patients with malignancies.

Introduction: Intrahepatic cholangiocarcinoma (IH-CCA) is a malignancy characterized with limited response to standard chemotherapeutic strategies due to development of drug resistance. We aim to investigate new immune-therapeutic strategy through using AUNP-12 as an immune checkpoint blocker in chemically induced IH-CCA mice model. Methods: Mice were randomly divided into 2 groups; normal control group and disease group. The disease group was further subdivided into 5 subgroups assigned according to treatment modality. The Immunotherapeutic mechanism of AUNP-12 was investigated through analysis of PD-1/PD-L1 levels and IFN-γ Levels in the tumor microenvironment. Immunohistochemical analysis of CD3+T lymphocytes and TGF-β was performed. Results: We reported that AUNP-12 significantly decreased levels of PD-1/PD-L1 at the site of tumor with subsequent activation of CD3+T lymphocytes that secrete IFN-γ which specifically lysis tumor cells. AUNP-12 also acts through downregulation of TGF-β signaling in IH-CCA mice group treated with AUNP-12. Conclusion: Our data indicated that AUNP-12 effectively harbors IH-CCA progression and improves the survival rate of mice. AUNP-12 acts as an immune check point blocker that specifically inhibits PD-1/PD-L1 binding, activates cytotoxic T-lymphocytes, and downregulates TGF-β signaling pathway.

Background Immune checkpoint blockade (ICB) therapy has demonstrated favorable clinical efficacy, particularly for advanced or difficult‐to‐treat cancer types. However, this therapy is ineffective for many patients displaying lack of immune response or resistance to ICB. This study aimed to establish a novel four‐gene signature (CD8A, CD8B, TCF7, and LEF1) to provide a prognostic immunotherapy biomarker for different cancers. Methods Transcriptome profiles and clinical data were obtained from The Cancer Genome Atlas database. Multivariate Cox regression analysis was used to establish a four‐gene signature. The R package estimate was used to obtain the immune score for every patient. Results Risk scores of the novel four‐gene signature could effectively divided all patients into high‐ and low‐risk groups, with distinct outcomes. The immune score calculated via the estimate package demonstrated that the four‐gene signature was significantly associated with the immune infiltration level. Furthermore, the four‐gene signature could predict the response to atezolizumab immunotherapy in patients with metastatic urothelial cancer. Conclusions The novel four‐gene signature developed in this study is a good prognostic biomarker, as it could identify many kinds of patients with cancer who are likely to respond to and benefit from immunotherapy. Multivariate Cox regression analysis was used to establish a novel four‐gene signature, which was significantly associated with the immune infiltration level. The four‐genesignature could predict the response to atezolizumab immunotherapy in patients withmetastatic urothelial cancer. The novel four‐gene signature developed in this study isa good prognostic biomarker, as it could identify many kinds of patients with cancerwho are likely to respond to and benefit from immunotherapy.

Resistance to programmed‐death‐1/programmed‐death‐ligand‐1 (PD‐1/PD‐L1) blockade in non‐small‐cell lung cancer (NSCLC) arises mainly from weak tumor immunogenicity and limited effector T‐cell infiltration. Here, this work presents an intravenously deliverable “living medicine” that addresses these barriers through biomimetic cloaking, tumor‐penetrating guidance, and synthetic‐biology‐driven cytokine release. Lactococcus lactis is engineered to co‐secrete Flt3L and OX40L (FOLactis) and then camouflage with red‐blood‐cell membranes, producing long‐circulating mRBC@FOLactis. Conjugation of the iRGD peptide (iRGD‐mRBC@FOLactis) enables trans‐endothelial migration and deep (≥200 µm) interstitial penetration, yielding a fourfold increase in intratumorally bacterial accumulation versus unmodified FOLactis. In the orthotopic Lewis lung carcinoma (LLC) model, a single intravenous dose of iRGD‐mRBC@FOLactis combined with anti‐PD‐1 antibody achieves complete tumor regression in 60% of mice, doubles median survival (p < 0.001), and generates systemic tumor‐specific immune memory. Mechanistically, local Flt3L and OX40L secretion expands cross‐presenting dendritic cells (DCs), boosts CD8⁺ T‐cell priming, and converts immunologically “cold” tumors into inflamed, T‐cell‐rich lesions, thereby overcoming primary resistance to checkpoint blockade. This multifunctional probiotic platform establishes a generalizable strategy for systemic delivery of living therapeutics and offers a powerful adjunct to PD‐1/PD‐L1 blockade for NSCLC and other treatment‐resistant solid tumors. This study presents an engineered probiotic platform, iRGD‐mRBC@FOLactis, combining red blood cell membrane cloaking and tumor‐penetrating peptide iRGD for enhanced PD‐1 blockade. The platform improves tumor targeting, immune cell activation and therapeutic efficacy in lung cancer, demonstrating significant promise in overcoming PD‐1/PD‐L1 therapy resistance. Created with BioRender.com.

Immune checkpoint blockade (ICB) therapies, such as immune checkpoint inhibitors against programmed death ligand-1 (PD-L1), have not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Despite the critical role of PD-L1 in various types of cancers, the regulatory mechanism of PD-L1 expression on the cell surface of PDAC is poorly understood. Therefore, uncovering potential modulators of cell surface localisation of PD-L1 may provide a new strategy to improve ICB therapy in patients with PDAC. Here, we examined the role of ezrin/radixin/moesin (ERM) family scaffold proteins that crosslink transmembrane proteins with the actin cytoskeleton in the surface localisation of PD-L1 in KP-2 cells, a human PDAC cell line. Our results demonstrated the abundant protein expression of PD-L1, ezrin, and radixin, but not moesin, as well as their colocalisation in the plasma membrane. Interestingly, immunoprecipitation analysis detected the molecular interaction of PD-L1 with ezrin and radixin. Moreover, gene silencing of ezrin moderately decreased the mRNA and cell surface expression of PD-L1, while that of radixin greatly decreased the surface expression of PD-L1 without altering the mRNA levels. Thus, radixin and ezrin differentially modulate the cell surface localisation of PD-L1 in KP-2 cells, highlighting a potential therapeutic target to improve the current ICB therapy in PDAC.

Whole-brain radiotherapy (WBRT) remains an essential modality of treatment for brain metastases (BMs) derived from non-small cell lung cancer (NSCLC) patients and anti-PD-1 therapy has demonstrated intracranial responses in these patients. We aimed to evaluate if the combination of the two treatments could yield additive efficacy. A retrospective review of our institution's database was carried out to identify NSCLC patients with BMs who had been treated with anti-PD1 therapy and/or WBRT between 2015 and 2020. Patient characteristics, main outcomes, including progression-free survival (PFS) and overall survival (OS), and factors affecting these outcomes were analyzed. SPSS 24 was used for statistical analysis. Appropriate statistical tests were employed according to the type of data. Overall, 21 NSCLC BM patients were identified that had received WBRT. Of these, ten had been additionally treated with anti-PD1 therapy within 30 days of WBRT initiation. Median PFS was 3 (95% CI 0.8-5.1) months with WBRT alone versus 11 (95% CI 6.3-15.6) months with combined treatment. Risk of disease progression was 71% lower with the combined approach (HR 0.29, 95% CI 0.11-0.80; =0.016). A trend toward improved OS was also observed with the combined approach (HR 0.33, 95% CI 0.08-1.12; =0.107). Concurrent treatment ( =0.028) and male sex ( =0.052) were associated with improved PFS, while OS was associated only with age ( =0.02). Concurrent WBRT and anti-PD1 therapy may delay progression and improve survival in BM patients with confirmed EGFR- and ALK-negative NSCLC histology. Prospective studies are warranted to validate and elucidate on the additive effect of the two modalities.

Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.