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The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells — namely, chimeric antigen receptor T cells — that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.Successful adoptive cell therapy for cancer depends on the expansion and persistence of tumour-specific T cells with stem-like memory or precursor characteristics. Here, the authors describe approaches to generate these cells by in vitro culture methods, by modulating transcriptional, metabolic and/or epigenetic programming, and by fine-tuning antigen receptor signalling.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma 1 – 4 , but the efficacy of CAR T cell therapy in solid tumours has been limited 5 . This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more ‘stem-like’ phenotype and increased mitochondrial mass 6 – 8 . We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours. Increased effectiveness of anti-cancer chimeric antigen receptor T cell therapy is associated with a stem-like phenotype through increased expression of FOXO1.

Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy. Immunoselection underpins tumor antigenic variability and is a key impediment to adoptive cell therapies. Darcy, Beavis and colleagues use T cells engineered to express the dendritic cell growth factor Flt3L to co-opt the host endogenous adaptive immune response and control experimental tumor models.

Combined targeting of angiogenic and immune pathways is an emerging strategy in clear cell carcinomas arising from the gynaecological tract (CCGCs), given the unique molecular and microenvironmental features of this gynaecological cancer. We aimed to evaluate the preliminary activity and safety of pembrolizumab plus lenvatinib in patients with recurrent CCGC. We conducted a multicentre, single-arm, phase 2 trial (LARA) across three tertiary hospitals in Singapore and South Korea. Adult patients (aged ≥18 years) with histologically confirmed CCGC, which had progressed or recurred after at least one previous line of platinum-based chemotherapy; an Eastern Cooperative Oncology Group performance status score of 0–1; and no previous exposure to immune checkpoint inhibitor therapy were eligible for inclusion. Patients received 200 mg intravenous pembrolizumab every 3 weeks plus 20 mg oral lenvatinib daily, until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurred first, for up to 2 years. The primary endpoint was objective response rate in the first 24 weeks of treatment, as per investigator-assessed Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov (NCT04699071) and is ongoing. Between March 26, 2021, and Oct 10, 2023, 30 patients were assessed for eligibility, of whom 27 (90%) participants received at least one dose of pembrolizumab plus lenvatinib. 25 (83%) patients were included in the primary outcome analysis. Median participant age was 52 years (IQR 40–66). Among the 27 patients, 12 (44%) were Chinese, 12 (44%) were Korean, two (7%) were Malay, and one (4%) was Filipino. 24 (89%) patients had primary ovarian clear cell carcinoma; three (11%) had primary endometrial cancer. All tumours had proficient mismatch repair or microsatellite stability. At data cutoff on March 19, 2025, median follow-up was 21·0 months (IQR 12·5–25·2). Ten of 25 patients had confirmed objective response within 24 weeks (objective response rate at 24 weeks 40% [95% CI 21–61]). Grade 3–4 treatment-related adverse events occurred in 14 (52%) of 27 patients, the most common of which were hypertension (six [22%] patients), decreased platelet count (two [7%]), elevated aspartate aminotransferase (AST; two [7%]), and elevated alanine aminotransferase (ALT; two [7%]). Serious adverse events occurred in five (19%) patients, the most common of which were immune-related hepatitis in two (7%) patients and decreased platelet count in two (7%) patients. No treatment-related deaths occurred. Pembrolizumab plus lenvatinib showed promising anti-tumour activity and manageable safety in patients with recurrent CCGC, including in patients with disease progression following previous treatment with anti-angiogenic therapy. These findings support further evaluation of this combination in randomised controlled trials. National Medical Research Council (Singapore), Pangestu Family Foundation Gynaecological Cancer Research Fund, and MSD.

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment. Mucosal-associated invariant T (MAIT) cells facilitate anti-microbial responses, but their functions in cancer protection is unclear. Here the authors show that activated MAIT cells induce an IFN-γ transcriptome in natural killer (NK) cells and enhance NK-dependent anti-cancer immunity in mice, thereby hinting a new avenue for cancer therapy.

Multiomic analyses have shed light upon the molecular heterogeneity and complexity of triple-negative breast cancers (TNBCs). With increasing recognition that TNBC is not a single disease entity but encompasses different disease subtypes, a one-size-fits-all treatment paradigm has become obsolete. In this context, the inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and androgen receptor (AR) signaling pathways have emerged as potential therapeutic strategies against selected tumors. In this paper, we reviewed the preclinical rationale, predictive biomarkers, efficacy, and safety data from early phase trials, and the future directions for these two biomarker-directed treatment approaches in TNBC.

The efficacy of Chimeric Antigen Receptor T cells against solid tumors is limited by immunosuppressive factors in the tumor microenvironment including adenosine, which suppresses Chimeric Antigen Receptor T cells through activation of the A 2A receptor. To overcome this, Chimeric Antigen Receptor T cells are engineered to express A 1 receptor, a receptor that signals inversely to A 2A receptor. Using murine and human Chimeric Antigen Receptor T cells, constitutive A 1 receptor overexpression significantly enhances Chimeric Antigen Receptor T cell effector function albeit at the expense of Chimeric Antigen Receptor T cell persistence. Through a CRISPR/Cas9 homology directed repair “knock-in” approach we demonstrate that Chimeric Antigen Receptor T cells engineered to express A 1 receptor in a tumor-localized manner, enhances anti-tumor therapeutic efficacy. This is dependent on the transcription factor IRF8 and is transcriptionally unique when compared to A 2A receptor deletion. This data provides a novel approach for enhancing Chimeric Antigen Receptor T cell efficacy in solid tumors and provides proof of principle for site-directed expression of factors that promote effector T cell differentiation. The efficacy of CAR-T cells against solid tumors is still limited by immunosuppressive factors. Here, the authors show that engineering of CAR T cells with A1R enhances their efficacy against solid tumors in vitro and in vivo.

Responses of solid tumors to chimeric antigen receptor (CAR) T cell therapy are often minimal. This is potentially due to a lack of sustained activation and proliferation of CAR T cells when encountering antigen in a profoundly immunosuppressive tumor microenvironment. In this study, we investigate if inducing an interaction between CAR T cells and antigen-presenting cells (APCs) in lymphoid tissue, away from an immunosuppressive microenvironment, could enhance solid-tumor responses. We combined CAR T cell transfer with the bacterial enterotoxin staphylococcal enterotoxin-B (SEB), which naturally links a proportion of T cell receptor (TCR) Vβ subtypes to MHC-II, present on APCs. CAR T cell proliferation and function was significantly enhanced by SEB. Solid tumor-growth inhibition in mice was increased when CAR T cells were administered in combination with SEB. CAR T cell expansion in lymphoid tissue was demonstrated, and inhibition of lymphocyte egress from lymph nodes using FTY720 abrogated the benefit of SEB. We also demonstrate that a bispecific antibody, targeting a c-Myc tag on CAR T cells and cluster of differentiation 40 (CD40), could also enhance CAR T cell activity and mediate increased antitumor activity of CAR T cells. These model systems serve as proof-of-principle that facilitating the interaction of CAR T cells with APCs can enhance their ability to mediate antitumor activity.

Fomite transmission contributes to the spread of many infectious diseases. However, pathogens in fomite transmission typically are either investigated individually without considering the context of native microbiotas or investigated in a nondiscriminatory way from the dispersal of microbiotas. The invasion ecology principles illustrated in many ecosystems have not yet been explored in the context of fomite transmission. We hypothesized that invaders in fomite transmission are trackable, are neutrally distributed between hands and environmental surfaces, and exhibit a proximity effect. To test this hypothesis, a surrogate invader, Lactobacillus delbrueckii subsp. bulgaricus , was spread by a root carrier in an office housing more than 20 participants undertaking normal activities, and the microbiotas on skin and environmental surfaces were analyzed before and after invasion. First, we found that the invader was trackable. Its identity and emission source could be determined using microbial-interaction networks, and the root carrier could be identified using a rank analysis. Without prior information, L. bulgaricus could be identified as the invader emitted from a source that exclusively contained the invader, and the probable root carrier could be located. In addition to the single-taxon invasion by L. bulgaricus , multiple-taxon invasion was observed, as genera from sputum/saliva exhibited co-occurrence relationships on skin and environmental surfaces. Second, the invader had a below-neutral distribution in a neutral community model, suggesting that hands accrued heavier invader contamination than environmental surfaces. Third, a proximity effect was observed on a surface touch network. Invader contamination on surfaces decreased with increasing geodesic distance from the hands of the carrier, indicating that the carrier’s touching behaviors were the main driver of fomite transmission. Taken together, these results demonstrate the invasion ecology principles in fomite transmission and provide a general basis for the management of ecological fomite transmission. IMPORTANCE Fomite transmission contributes to the spread of many infectious diseases. However, pathogens in fomite transmission typically are either investigated individually without considering the context of native microbiotas or investigated in a nondiscriminatory way from the dispersal of microbiotas. In this study, we adopted an invasion ecology framework in which we considered pathogens as invaders, the surface environment as an ecosystem, and human behaviors as the driver of microbial dispersal. With this approach, we assessed the ability of quantitative ecological theories to track and forecast pathogen movements in fomite transmission. By uncovering the relationships between the invader and native microbiotas and between human behaviors and invader/microbiota dispersal, we demonstrated that fomite transmission follows idiosyncratic invasion ecology principles. Our findings suggest that attempts to manage fomite transmission for public health purposes should focus on the microbial communities and anthropogenic factors involved, in addition to the pathogens.

Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients with hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression treatment regimens and their sequencing continue to evolve in the rapidly changing treatment landscape. In this review, we summarize the mechanisms of resistance to ET and CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators and activation of alternative signaling pathways. Recent clinical trials have been directed at the targets and pathways implicated, including estrogen and androgen receptors, PI3K/AKT/mTOR and MAPK pathways, tyrosine kinase receptors such as FGFR and HER2, homologous recombination repair pathway, other components of the cell cycle and cell death. We describe the findings from these clinical trials using small molecule inhibitors, antibody–drug conjugates and immunotherapy, providing insights into how these novel strategies may circumvent treatment resistance, and discuss how some have not translated into clinical benefit. The challenges posed by tumor heterogeneity, adaptive rewiring of signaling pathways and dose-limiting toxicities underscore the need to elucidate the latest tumor biology in each patient, and develop treatments with improved therapeutic index in the era of precision medicine.