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Patients who had had a relapse after receiving platinum-containing chemotherapy and a PD-1 or PD-L1 immune checkpoint inhibitor were assigned to receive enfortumab vedotin or one of three chemotherapy agents chosen by their doctor. Enfortumab vedotin prolonged progression-free and overall survival.

Lenvatinib plus either pembrolizumab or everolimus was compared with sunitinib as first-line therapy for advanced renal cell cancer. Progression-free survival was significantly longer with lenvatinib plus pembrolizumab than with sunitinib. Lenvatinib plus everolimus was also more effective than sunitinib, but the difference was smaller.

(B, C) After pre-treatment with GSK (1 μM) for 90 min, cells (LRRK2 WT RAW 264.7 and HMC3) were exposed to Mn for designated time periods, followed by the MTT assay to determine cell viability, as described in the Methods section, @@@, p < 0.001; @@, p < 0.01; ***, p < 0.001 compared to the control (one-way ANOVA followed by Tukey’s post hoc test; n = 3, apoptosis assay; n = 6, MTT assay). The authors comment that the flow cytometry machine and program used for the experiment presented the imaging data in a clockwise quadrant image arrangement; Q1 is top left, Q2 is top right, Q3 is bottom right, and Q4 is bottom left, which was not clearly annotated in the original article. Because of the missing quadrant annotation, the published figure legends for Figs 2 and 3 could be misinterpreted. The authors’ explanation, the gating strategy (S1 File), and the underlying data provided for Figs 2 and 3 (S2–S4 Files) were reviewed by an independent member of the PLOS One Editorial Board and an independent FACS expert, who concluded that the data provided (S1–S4 Files) appear to support the published results.

[This corrects the article DOI: 10.1371/journal.ppat.1012387.].

Autophagy plays a critical role in maintaining cellular homeostasis and is implicated in various physiological and pathological processes, including cancer, neurodegeneration, and metabolic disorders. Although typically associated with cell survival, autophagy has also been proposed to contribute to cell death, referred to as autophagic cell death (ACD). However, the identification of ACD remains contentious due to inconsistencies in experimental methodologies and terminological misuse. In this study, we systematically evaluated 104 research articles published in 2022 that claimed to demonstrate ACD. Articles were assessed based on established criteria, including evidence for autophagy, evidence for cell death, exclusion of apoptosis, and experimental designs demonstrating causality. Our findings reveal that only 12.5% of the articles fulfilled all ACD criteria, while 37.5% provided only correlation‐level evidence. Additionally, 54.81% failed to demonstrate autophagy flux, 32.7% relied on viability loss rather than direct evidence of cell death, and 45.0% of studies utilizing autophagy inhibition failed to demonstrate actual inhibition of autophagy. Inconsistent terminology was also prevalent, with “autophagy‐mediated cell death” often misclassified as ACD and ACD frequently misused to describe autophagy co‐occurring with cell death. These issues highlight a lack of rigor in current practices, with correlation‐level evidence, inappropriate experimental designs, and terminological misuse undermining study robustness. To address these challenges, we developed a systematic workflow providing experimental and analytical guidance for classifying evidence for different modes of autophagy. Our analysis underscores the need for greater rigor, standardized approaches, and precise terminology to advance understanding of the interplay between autophagy and cell death. Of 104 studies claiming autophagic cell death (ACD), only 13 demonstrated both causality and exclusion of apoptosis to confirm true ACD. Most studies relied on correlation‐level data or measured autophagy in isolation, revealing pervasive methodological shortcomings.

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC′ and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1’s affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC′ and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC′ loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.

Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1 + CD8 + T cells relative to that of PD-1 + regulatory T (T reg ) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8 + T cells and T reg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1 + CD8 + T cells and enhanced PD-1 + T reg cell–mediated immunosuppression. A profound reactivation of effector PD-1 + CD8 + T cells rather than PD-1 + T reg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies. Checkpoint blockade is effective in only a subset of patients; therefore, biomarkers that can predict efficacy would be clinically highly valuable. Nishkawa and colleagues develop a biomarker based on PD-1 positivity of effector and regulatory T cells in the tumor microenvironment that accurately predicts the effectiveness of checkpoint blockade in patients.

Spinal cord injury (SCI) always leads to functional deterioration due to a series of processes including cell death. In recent years, programmed cell death (PCD) is considered to be a critical process after SCI, and various forms of PCD were discovered in recent years, including apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis. Unlike necrosis, PCD is known as an active cell death mediated by a cascade of gene expression events, and it is crucial for elimination unnecessary and damaged cells, as well as a defence mechanism. Therefore, it would be meaningful to characterize the roles of PCD to not only enhance our understanding of the pathophysiological processes, but also improve functional recovery after SCI. This review will summarize and explore the most recent advances on how apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis are involved in SCI. This review can help us to understand the various functions of PCD in the pathological processes of SCI, and contribute to our novel understanding of SCI of unknown aetiology in the near future. Different types of programmed cell death (PCD) play different roles in spinal cord injury. PCD is an active cell death mediated by a cascade of gene expression events, and it is crucial for elimination unnecessary and damaged cells, as well as a defense mechanism. PCD consists of a series of activities, such as apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis. This figure indicates how how apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis are involved in spinal cord injury.

Despite the success of PD-1 blockade in cancer therapy, how PD-1 initiates signaling remains unclear. Soluble PD-L1 is found in patient sera and can bind PD-1 but fails to suppress T cell function. Here, we show that PD-1 function is reduced when mechanical support on ligand is removed. Mechanistically, cells exert forces to PD-1 and prolong bond lifetime at forces <7 pN (catch bond) while accelerate dissociation at forces >8pN (slip bond). Molecular dynamics of PD-1–PD-L2 complex suggests force may cause relative rotation and translation between the two molecules yielding distinct atomic contacts not observed in the crystal structure. Compared to wild-type, PD-1 mutants targeting the force-induced distinct interactions maintain the same binding affinity but suppressed/eliminated catch bond, lowered rupture force, and reduced inhibitory function. Our results uncover a mechanism for cells to probe the mechanical support of PD-1–PD-Ligand bonds using endogenous forces to regulate PD-1 signaling. Despite the success of PD-1 blockade in cancer therapy, how PD-1 initiates signalling remains unclear. Here the authors show that PD-1 function is reduced when mechanical support on ligand is removed.