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Key Points Exploration for biomarkers for drugs that block immune checkpoints should be rationally conducted based on knowledge of the mechanism of action of the targeted pathway. The programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated antigen 4 (CTLA4) pathways are unique, and there are special considerations based on mechanisms of action for developing biomarkers for drugs blocking each of these pathways. Biomarkers for immune checkpoint-blocking drugs currently fall into three major categories: immunological, genetic and virological. Future work may reveal additional markers related to metabolism and the microbiome. Immunological biomarkers offer the advantage of applicability across multiple tumour types amenable to immune checkpoint blockade. In the case of anti-PD1 drugs, tumour PD1 ligand 1 (PDL1) expression is a pretreatment biomarker that predicts a greater likelihood of response to therapy. Despite technical pitfalls that make clinical application challenging, two PDL1 immunohistochemistry tests are currently approved by the US Food and Drug Administration for guiding treatment decisions in patients with non-small-cell lung cancer and melanoma. Although no specific oncogene or driver mutation has yet been correlated with clinical response to immune checkpoint blockade, overall tumour mutational burden reflecting neoantigenic diversity may have predictive value. This is exemplified by the high anti-PD1 response rate in DNA mismatch repair deficient colorectal cancers (which have a large mutational burden and which account for ∼15% of all colon cancers), whereas mismatch repair proficient colon cancers are unlikely to respond. Virus-associated cancers, which account for more than 20% of cancers worldwide, express viral neoantigens that are strongly immunogenic. Early evidence demonstrates expression of PD1–PDL1 in these cancers, and suggests responsiveness to anti-PD1 therapies. Combination treatment regimens based on immune checkpoint-blocking drugs are emerging as the next step in clinical development to improve efficacy and response durability. Biomarker considerations for these regimens are complex and are likely to involve multifactorial assessments. This Review assesses the mechanism-based biomarkers in use and in development for immune checkpoint inhibition, identifying cancer types and cancer phenotypes that are most likely to respond to immune checkpoint blockade, and considerations for future biomarkers of immune checkpoint response. With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0–100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0–5%, >5–30%, >30–80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 . Analysis of the phase 3 CheckMate 816 trial shows that the depth of pathologic response as assessed by percent residual viable tumor is correlated with event-free survival following neoadjuvant immunotherapy plus chemotherapy, supporting pathologic response as a biomarker of survival.

Lymphocyte Activation Gene - 3 (LAG-3) is an immune checkpoint molecule that regulates both T-cell activation and homeostasis. However, the molecular mechanisms underlying LAG-3's function are generally unknown. Using a model in which LAG-3 blockade or absence reliably augmented homeostatic proliferation in vivo, we found that IL-2 and STAT5 are critical for LAG-3 function. Similarly, LAG-3 blockade was ineffective in the absence of regulatory T-cells (Treg), suggesting an important role for LAG-3 in either the responsiveness of conventional T-cells (Tconv) to regulation, or a relative defect in the ability of LAG-3 KO regulatory T-cells (Treg) to suppress the proliferation of Tconv. In this model, LAG-3 KO Treg suppressed proliferation in a manner fairly similar to wild-type (WT) Treg, but LAG-3 KO Tconv were relatively resistant to suppression. Further studies also identified a role for LAG-3 in the induction/expansion of Treg. Finally, we found that LAG-3 blockade (or knockout) led to a relative skewing of naïve CD4 T-cells toward a TH1 phenotype both in vitro and in in vivo. Together, these data suggest that LAG-3 expression on Tconv cells makes them more susceptible to Treg based suppression, and also regulates the development of a TH1 T-cell response.

ObjectiveRecent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival.DesignThirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein–Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour–stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density.Results12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS).ConclusionsPD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.

Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an ‘Immunoscore’, which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies.

Immune checkpoint inhibitors block the co-inhibitory receptors on T cells to activate their cytotoxic immune function and are rapidly being explored for the treatment of various advanced-stage malignancies. These novel drugs have already significantly increased survival rates. The first available immune checkpoint inhibitors were cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors (such as ipilimumab), followed by programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors (such as pembrolizumab and nivolumab). Anti-PD-1 and anti-PD-L1 therapies have demonstrated better efficacy and tolerability and less severe adverse effects compared to anti-CTLA-4 agents. Idelalisib, a PI3Kδ isoform inhibitor, is another immunotherapeutic agent that is often classified separately and is currently used in treatment of chronic lymphocytic leukemia and non-Hodgkin lymphomas. Despite successful therapeutic responses, immune-related adverse events have been reported with the use of these agents. The gastrointestinal side effects, particularly diarrhea, are among the most commonly reported symptoms. The histologic features of immune checkpoint inhibitor-associated colitis show a spectrum of patterns of injury among various drug classes. There is significant overlap between immune checkpoint inhibitor-associated colitis and other colitides, making the differential diagnosis difficult—especially in the absence of clinical history. The histopathology data on immune checkpoint inhibitor-associated colitis are limited. Here we review clinical features as well as various histologic patterns of colitis associated with these groups of medications.

Programmed death-ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1-negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti-PD-L1-mediated therapy in 2 different murine tumor models. Using real-time imaging in whole tumor tissues, we found that anti-PD-L1 Ab accumulates in tumor tissues, regardless of the status of PD-L1 expression on tumor cells. We further observed that, while PD-L1 on tumor cells was largely dispensable for the response to checkpoint blockade, PD-L1 in host myeloid cells was essential for this response. Additionally, PD-L1 signaling in defined antigen-presenting cells (APCs) negatively regulated and inhibited T cell activation. PD-L1 blockade inside tumors was not sufficient to mediate regression, as limiting T cell trafficking reduced the efficacy of the blockade. Together, these findings demonstrate that PD-L1 expressed in APCs, rather than on tumor cells, plays an essential role in checkpoint blockade therapy, providing an insight into the mechanisms of this therapy.

International policy frameworks, including the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) and the WHO Quality Rights initiative, have established dignity as a foundational right in mental health care. However, a significant gap remains between these policy aspirations and the lived experience of service users, often due to risk-averse cultures that prioritize control over autonomy. This commentary employs an interpretive synthesis of international literature (2006–2025) and illustrative case examples, such as the Trieste model and Quality Rights implementation in low-resource settings, to examine the operationalization of dignity-centered care. I argue for a paradigm shift from control-based safety models to relational safety grounded in biographical literacy and positive risk-taking. Key findings highlight that dignity-centered approaches not only improve patient experiences of respect and agency but also mitigate moral injury and burnout among the nursing workforce. Furthermore, as digital mental health tools and AI-driven risk assessments emerge, systems must ensure these technologies enhance rather than automate paternalism. I conclude that realizing dignity-centered care requires a structural and cultural transformation, embedding dignity into clinical protocols, leadership practices, and environmental design to move beyond rhetorical commitments toward measurable, humane standards.

Unsafe care remains a major global health challenge, contributing to millions of preventable deaths and ranking among the top ten causes of mortality and disability worldwide. The World Health Organization's Global Patient Safety Action Plan 2021-2030 emphasizes the need for strong leadership and system-wide engagement to eliminate avoidable harm. As the largest component of the global healthcare workforce, nurses-especially those in management roles-are essential to achieving these goals. Objective: This narrative review synthesizes global evidence on how nursing management practices, particularly leadership, staffing, and safety culture, influence patient safety outcomes across diverse health systems. A purposive narrative review was conducted using PubMed, CINAHL, Scopus, and Web of Science databases. Peer-reviewed studies and organizational reports published between 2020 and 2025 were evaluated. A thematic synthesis approach was used to identify patterns related to leadership style, staffing ratios, workplace conditions, and organizational resilience. Quality appraisal followed adapted Critical Appraisal Skills Programme (CASP) and Joanna Briggs Institute (JBI) guidance. A total of 37 peer-reviewed empirical studies were included in the narrative synthesis, along with key global policy and foundational framework documents used to contextualize findings. Evidence consistently demonstrated that transformational leadership, adequate nurse staffing, positive safety culture, and organizational learning structures are strongly associated with improved patient outcomes, reduced errors, and enhanced workforce well-being. Most studies exhibited moderate to high methodological rigor. Nursing management plays a decisive role in advancing global patient safety. Policies that strengthen leadership capacity, ensure safe staffing, promote just culture, and support nurse well-being are critical to achieving WHO's 2030 safety objectives. Empowering nurse leaders across all regions is essential for building safer, more resilient health systems.

Mucus-invasive bacterial biofilms are identified on the colon mucosa of approximately 50% of colorectal cancer (CRC) patients and approximately 13% of healthy subjects. Here, we test the hypothesis that human colon biofilms comprise microbial communities that are carcinogenic in CRC mouse models. Homogenates of human biofilm-positive colon mucosa were prepared from tumor patients (tumor and paired normal tissues from surgical resections) or biofilm-positive biopsies from healthy individuals undergoing screening colonoscopy; homogenates of biofilm-negative colon biopsies from healthy individuals undergoing screening colonoscopy served as controls. After 12 weeks, biofilm-positive, but not biofilm-negative, human colon mucosal homogenates induced colon tumor formation in 3 mouse colon tumor models (germ-free ApcMinΔ850/+;Il10-/- or ApcMinΔ850/+ and specific pathogen-free ApcMinΔ716/+ mice). Remarkably, biofilm-positive communities from healthy colonoscopy biopsies induced colon inflammation and tumors similarly to biofilm-positive tumor tissues. By 1 week, biofilm-positive human tumor homogenates, but not healthy biopsies, displayed consistent bacterial mucus invasion and biofilm formation in mouse colons. 16S rRNA gene sequencing and RNA-Seq analyses identified compositional and functional microbiota differences between mice colonized with biofilm-positive and biofilm-negative communities. These results suggest human colon mucosal biofilms, whether from tumor hosts or healthy individuals undergoing screening colonoscopy, are carcinogenic in murine models of CRC.