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Cancer immunotherapy is a novel pillar of cancer treatment that harnesses the immune system to fight tumors and generally results in robust antitumor immunity. Although immunotherapy has achieved remarkable clinical success for some patients, many patients do not respond, underscoring the need to develop new strategies to promote antitumor immunity. Pyroptosis is an immunostimulatory type of regulated cell death that activates the innate immune system. A hallmark of pyroptosis is the release of intracellular contents such as cytokines, alarmins, and chemokines that can stimulate adaptive immune activation. Recent studies suggest that pyroptosis promotes antitumor immunity. Here, we review the mechanisms by which pyroptosis can be induced and highlight new strategies to induce pyroptosis in cancer cells for antitumor defense. We discuss how pyroptosis modulates the tumor microenvironment to stimulate adaptive immunity and promote antitumor immunity. We also suggest research areas to focus on for continued development of pyroptosis as an anticancer treatment. Pyroptosis-based anticancer therapies offer a promising new avenue for treating immunologically ‘cold’ tumors.

Caspases are a family of cysteine proteases that act as molecular scissors to cleave substrates and regulate biological processes such as programmed cell death and inflammation. Extensive efforts have been made to identify caspase substrates and to determine factors that dictate substrate specificity. Thousands of putative substrates have been identified for caspases that regulate an immunologically silent type of cell death known as apoptosis, but less is known about substrates of the inflammatory caspases that regulate an immunostimulatory type of cell death called pyroptosis. Furthermore, much of our understanding of caspase substrate specificities is derived from work done with peptide substrates, which do not often translate to native protein substrates. Our knowledge of inflammatory caspase biology and substrates has recently expanded and here, we discuss the recent advances in our understanding of caspase substrate specificities, with a focus on inflammatory caspases. We highlight new substrates that have been discovered and discuss the factors that engender specificity. Recent evidence suggests that inflammatory caspases likely utilize two binding interfaces to recognize and process substrates, the active site and a conserved exosite.

Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient’s own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases.The synthetic enzyme-armed killer (SEAKER) approach equips chimeric antigen receptor (CAR)-T cells with the capacity to express enzymes that process anticancer prodrugs at tumor sites of action.

Inflammasomes are signaling platforms that activate inflammatory caspases to initiate innate immune responses. Canonical inflammasomes sense diverse threats and activate CASP1, which cleaves the pro-inflammatory cytokines IL-1β and IL-18 and the pore-forming protein gasdermin D (GSDMD) to induce pyroptosis. In contrast, the non-canonical inflammasome senses bacterial lipopolysaccharide (LPS) through CASP4 and CASP5 to induce pyroptosis. While CASP1 substrates are well defined, those of CASP4 and CASP5 remain less understood. Here, we show that intracellular LPS and the gram-negative bacterial pathogen Salmonella activate CASP4/5 in macrophages to directly cleave and activate CASP3 and CASP7. Activated CASP3 subsequently cleaves gasdermin E (GSDME). Surprisingly, CASP3, but not GSDME, was required for restricting intracellular Salmonella replication, suggesting a protective role for apoptotic signaling. We further find that most GSDMD cleavage during non-canonical signaling is mediated by CASP1. Consistent with this, loss of GSDMD, but not GSDME, reduced LDH release, establishing GSDMD as the primary driver of pyroptosis during LPS transfection. In contrast, during Salmonella infection, cell lysis occurred independently of both GSDMD and GSDME, suggesting the involvement of alternative lytic mechanisms. Finally, we demonstrate that CASP4/5 activation of CASP3/7 and GSDME occurs in human primary macrophages, defining CASP4/5 as dual apoptotic initiator and inflammatory caspases in innate immunity.

Sexually transmitted infection (STI) rates continue to rise in Australia, and timely access to testing and treatment is crucial to reduce transmission. Web-based services have been viewed as a way to improve timely access to STI/HIV testing and have proliferated in recent years. However, the regulation of these services in Australia is minimal, leading to concerns about their quality. The purpose of this review was to systematically identify web-based STI/HIV testing services available in Australia and assess them on aspects of quality, reliability, and accessibility. We aim to systematically identify and assess web-based STI/HIV testing services available in Australia. A Google search of Australian web-based services was conducted in March 2022 and repeated in September 2022 using Boolean operators and search terms related to test services (eg, on the internet or home), STIs (eg, chlamydia or gonorrhea), and test type (eg, self-test). The first 10 pages were assessed, and services were categorized as self-testing (ST; test at home), self-sampling (SS; sample at home and return to laboratory), or self-navigated pathology (SNP; specimens collected at pathology center). Website reliability was assessed against the Health on the Net Foundation code of conduct, and service quality was assessed using a scorecard that was developed based on similar reviews, Australian guidelines for in-person services, and UK standards. Additionally, we looked at measures of accessibility including cost, rural access, and time to test results. Seventeen services were identified (8 ST, 2 SS, and 7 SNP). Only 4 services offered recommended testing for all 4 infections (chlamydia, gonorrhea, syphilis, and HIV) including genital, anorectal, and oropharyngeal sites, and 5 offered tests other than those recommended by Australian testing guidelines (eg, Ureaplasma). Nine services (1 SNP, 8 self-test) had no minimum age requirements for access. Reliability scores (scale 0-8) were similar between all services (range 4.75-8.0). Quality weighted scores (scale 0-58) were similar between SNP and SS services (average 44.89, SD 5.56 and 44.75, SD 1.77, respectively) but lower for ST services (22.66, SD 8.93; P=.002). Government-funded services were of higher quality than private services (43.54, SD 6.71 vs 29.43, SD 13.55; P=.03). The cost for services varied between SNP (Aus0- 595; ie, US0- 381.96), self-sample (Aus0; ie, US 0), and ST (Aus0- 135; ie, US0- 86.66). The time to test results was much shorter for SNP services ( 4 days) than for SS ( 12 days) and ST ( 14 days). This review identified considerable variability in the quality and reliability of the web-based STI/HIV testing services in Australia. Given the proliferation and use of these services will likely increase, it is imperative that Australia develops national standards to ensure the standard-of-care offered by web-based STI/HIV testing services is appropriate to protect Australian users from the impact of poorly performing and inappropriate tests.

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.

This paper examines factors that enabled successful integration of testing for sexually transmissible infections into routine care in Aboriginal Community Controlled Health Services. This paper reports analysis of qualitative interview data recorded with 19 purposively sampled key informants in New South Wales, Australia, representing six Aboriginal Community Controlled Health Services and five government health bodies supporting those services. The analysis explicitly adopted a strengths‐based approach. Participants reported a strong belief that routine screening overcomes shame and increases engagement with sexual health screening. Incorporating sexual health screening into general medical consultations increases the capture of asymptomatic cases. The Medicare Benefits Schedule 715 Adult Health Check was highlighted as an ideal lever for effective integration into routine care. Integration of testing for sexually transmissible infections into routine care is widely perceived as best practice by senior stakeholders in Aboriginal healthcare in NSW. Findings support continued work to optimise the MBS 715 as a lever to increase testing. Identifying accessible strategies to increase testing for sexually transmissible infections in Aboriginal Community Controlled Health Services can reduce disparities in notifications affecting Aboriginal young people.

Examine the changes in service delivery Australian public sexual health clinics made to remain open during lockdown. A cross‐sectional survey designed and delivered on Qualtrics was emailed to 21 directors of public sexual health clinics across Australia from July‐August 2020 and asked about a variety of changes to service delivery. Descriptive statistics were calculated. Twenty clinics participated, all remained open and reported service changes, including suspension of walk‐in services in eight clinics. Some clinics stopped offering asymptomatic screening for varying patient populations. Most clinics transitioned to a mix of telehealth and face‐to‐face consultations. Nineteen clinics reported delays in testing and 13 reported limitations in testing. Most clinics changed to phone consultations for HIV medication refills (n=15) and eleven clinics prescribed longer repeat prescriptions. Fourteen clinics had staff redeployed to assist the COVID‐19 response. Public sexual health clinics pivoted service delivery to reduce risk of COVID‐19 transmission in clinical settings, managed staffing reductions and delays in molecular testing, and maintained a focus on urgent and symptomatic STI presentations and those at higher risk of HIV/STI acquisition. Further research is warranted to understand what impact reduced asymptomatic screening may have had on community STI transmission.

Introduction Gay, bisexual and other men who have sex with men are disproportionately affected by HIV and other sexually transmitted infections (STIs). This study explores preferences for different models of sexual health services among gay, bisexual and other men who have sex with men in Australia, using discrete choice experiments (DCEs). Methods A cross‐sectional online survey was conducted from November 2022 to February 2023, targeting three groups: (1) gay, bisexual and other men who have sex with men living with HIV; (2) pre‐exposure prophylaxis (PrEP) users; and (3) non‐PrEP users. Participants were recruited through paid advertisements, sexual health clinics and community networks. The survey included demographic questions, sexual behaviour inquiries and three tailored DCEs to quantify preferences for service delivery attributes such as cost, type of clinic, appointment type, appointment frequency, extra services and where samples are taken for HIV/STI testing. We used latent class analyses to identify subgroups of people with similar preferences. Results We recruited 1422 participants. The median age was 41 (interquartile range [IQR]: 32–54) for gay, bisexual and other men who have sex with men living with HIV (N = 396), 35 (IQR: 29–45) for PrEP users (N = 436) and 33 (IQR: 26–44) for non‐PrEP users (N = 590). In our latent class analyses, gay, bisexual and other men who have sex with men living with HIV preferred sexual health services to be delivered via sexual health clinics (46.2%), general practitioners (GP) with expertise in lesbian, gay, bisexual, trans, queer and others (LGBTQ+) health (33.0%) or were happy to go anywhere and to pay (20.7%). PrEP users preferred either PrEP‐only clinics or GP with expertise in LGBTQ+ health (75.2%) and GP with expertise in LGBTQ+ health only (24.8%). Non‐PrEP users preferred GP with expertise in LGBTQ+ health (44.7%) or any free service (22.8%); some did not want to test (22.2%) or were unsure of their preferences (10.2%). Conclusions To align service models with client needs, investment in specialist sexual health clinics and LGBTQ+ competent GPs is important, though this may depend on local resources and infrastructure. Future research should focus on addressing financial barriers, evaluating telehealth and digital health interventions, and understanding testing reluctance among non‐PrEP users.

The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.