Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With the widespread use of the drug, we must deeply analyze the dilemma of the agents and seek a breakthrough in the treatment prospect. Over the past decades, these agents have demonstrated dramatic efficacy, especially in patients with melanoma and non-small cell lung cancer (NSCLC). Nonetheless, in the field of a broad concept of solid tumours, non-specific indications, inseparable immune response and side effects, unconfirmed progressive disease, and complex regulatory networks of immune resistance are four barriers that limit its widespread application. Fortunately, the successful clinical trials of novel ICB agents and combination therapies, the advent of the era of oncolytic virus gene editing, and the breakthrough of the technical barriers of mRNA vaccines and nano-delivery systems have made remarkable breakthroughs currently. In this review, we enumerate the mechanisms of each immune checkpoint targets, associations between ICB with tumour mutation burden, key immune regulatory or resistance signalling pathways, the specific clinical evidence of the efficacy of classical targets and new targets among different tumour types and put forward dialectical thoughts on drug safety. Finally, we discuss the importance of accurate triage of ICB based on recent advances in predictive biomarkers and diagnostic testing techniques.

Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.

Chimeric antigen receptor (CAR) T cell therapy is a new frontier in cancer therapy. The toxicity of cytokine release syndrome (CRS) has become one of the major challenges that limits the wider use of CAR T cells to fight cancer. Exploration of CRS pathogenesis and treatment is becoming the main focus of ongoing studies. Myeloid-derived macrophages were found to play a critical role in CRS pathogenesis, and these cells mediate the major production of core cytokines, including IL-6, IL-1 and interferon (IFN)-γ. Colocalization of macrophages and CAR T cells was also identified as necessary for inducing CRS, and CD40L-CD40 signaling might be the key cell–cell interaction in the tumor microenvironment. Macrophages might also take part in endocrine and self-amplified catecholamine loops that can directly activate cytokine production and release by macrophages during CRS. In addition to tocilizumab and corticosteroids, several novel CRS therapies targeting macrophage-centered pathways have shown much potential, including GM-CSF blockade and administration of atrial natriuretic peptide (ANP) and α-methyltyrosine (metyrosine, MTR). In the present review, we summarized the role of macrophages in CRS and new developments in therapeutic strategies for CRS-associated toxicities.

Myeloid-derived suppressor cells (MDSC) are a group of immature cells that produced by emergency myelopoiesis. Emerging evidences have identified the vital role of MDSC in cancer microenvironment, in which MDSC exerts both immunological and non-immunological activities to assist the progression of cancer. Advances in pre-clinical research have provided us the understanding of MDSC in cancer context from the perspective of molecular mechanism. In clinical scenario, MDSC and its subsets have been discovered to exist in peripheral blood and tumor site of patients from various types of cancers. In this review, we highlight the clinical value of MDSC in predicting prognosis of cancer patients and the responses of immunotherapies, therefore to propose the MDSC-inhibiting strategy in the scenario of cancer immunotherapies. Phenotypes and biological functions of MDSC in cancer microenvironment are comprehensively summarized to provide potential targets of MDSC-inhibiting strategy from the aspect of molecular mechanisms.

Heat shock proteins 70 (Hsp70) are required for key cellular processes and responses to environmental changes, however, there are an unknown number of hsp70 gene family members in the large yellow croaker (Larimichthys crocea). In the present study, 17 hsp70 genes were identified through the genome of the large yellow croaker. These genes are divided into seven evolutionarily distinct groups according to a phylogenetic tree. The orthologs of these hsp70 genes were found in humans and zebrafish. The expression patterns of the hsp70 gene family in the large yellow croaker under cold and heat stress were studied by examining transcriptome data. Six out of 17 genes were significantly unregulated or downregulated after cold or heat stress. There were two genes significantly upregulated and two genes downregulated in the liver after cold treatment, while after heat treatment, five genes were significantly upregulated, and no genes were significantly downregulated. Three expression patterns were detected: strictly heat-inducible hsp70, constitutively expressed and moderately heat-inducible hsp70, and constitutively expressed and less stress-dependent hsp70 genes. All the findings will contribute to a better understanding of the biological function of hsp70s in defending against thermal challenges.

Background: In addition to their established action of synthetic lethality in tumor cells, poly(ADP-ribose) polymerase inhibitors (PARPis) also orchestrate tumor immune microenvironment (TIME) that contributes to suppressing tumor growth. However, it remains not fully understood whether and how PARPis trigger tumor-targeting immune responses. Methods: To decode the immune responses reshaped by PARPis, we conducted T-cell receptor (TCR) sequencing and immunohistochemical (IHC) analyses of paired clinical specimens before and after niraparib monotherapy obtained from a prospective study, as well as ID8 mouse ovarian tumors. To validate the induction of immunogenic cell death (ICD) by PARPis, we performed immunofluorescence/IHC staining with homologous recombination deficiency tumor cells and patient-derived xenograft tumor tissues, respectively. To substantiate that PARPis elicited tumor cell pyroptosis, we undertook comprehensive assessments of the cellular morphological features, cleavage of gasdermin (GSDM) proteins, and activation of TNF-caspase signaling pathways through genetic downregulation/depletion and selective inhibition. We also evaluated the critical role of pyroptosis in tumor suppression and immune activation following niraparib treatment using a syngeneic mouse model with implanting CRISPR/Cas9 edited Gsdme^{−/ −} ID8 tumor cells into C57BL/6 mice. Results: Our findings revealed that PARPis augmented the proportion of neoantigen-recognized TCR clones and TCR clonal expansion, and induced an inflamed TIME characterized by increased infiltration of both innate and adaptive immune cells. This PARPis-strengthened immune response was associated with the induction of ICD, specifically identified as pyroptosis, which possessed distinctive morphological features and GSDMD/E cleavage. It was validated that the cleavage of GSDMD/E was due to elevated caspase 8 activity downstream of the TNFR1, rather than FAS and TRAIL-R. On PARP inhibition, the NF-κB signaling pathway was activated, leading to increased secretion of TNF-α and subsequent initiation of the TNFR1–caspase 8 cascade. Impeding pyroptosis through the depletion of Gsdme significantly compromised the tumor-suppressing effects of PARP inhibition and undermined the anti-immune response in the syngeneic ID8 mouse model. Conclusions: PARPis induce a specific type of ICD called pyroptosis via TNF–caspase 8–GSDMD/E axis, resulting in an inflamed TIME and augmentation of tumor-targeting immune responses. These findings deepen our understanding of PARPis activities and point toward a promising avenue for synergizing PARPis with immunotherapeutic interventions. Trial registration number: NCT04507841.