Abstract Resistance in breast cancer treatment drives the search for new therapies. Cancer stem cells (CSCs) contribute to metastasis, recurrence, and therapy resistance. Our data suggest that combining panobinostat, venetoclax, and anti-CD40 (aCD40) immunotherapy effectively eliminates CSCs through immune modulation. This triple combination showed superior outcomes in three breast cancer mouse models, though its precise mechanism remains unclear. To dissect these mechansims, we use a multiplex implantable microdevice assay (MIMA) for precise drug delivery, cyclic immunofluorescence for tumor microenvironment characterization, and computational analyses to investigate treatment response and resistance. Single-cell RNA sequencing and multiplex tissue imaging map drug-induced cellular changes. Our results demonstrate that the panobinostat and venetoclax combination (PV) increase intratumoral immune infiltration, recruiting neutrophils, macrophages, and dendritic cells (DCs). Spatial analysis reveals APOE+ myeloid cells accumulating in PV-treated regions. Systemic PVaCD40 treatment enhances tumor killing, reduces CSCs, and improves antigen presentation by activating DCs and macrophages. Mechanistically, macrophages upregulate interferon-induced genes, boosting antigen presentation, while DCs regulate T cell migration and also increase antigen presentation. Interactions between CSCs and DCs/macrophages are elevated, and ligand-receptor analyses indicate that Mif-Cd74 and App-Cd74 signaling mediate CSC-immune cell communication. Collectively, these results provide a mechanistic framework for how Panobinostat-Venetoclax-Anti-CD40 triple combination therapy remodels the tumor microenvironment to eliminate breast CSCs and potentiate antitumor immunity. Citation Format: Yishu Xu, Juraj Jakubik, Leoni Moldaner, Gautami Atul Gaidhani, Zuzana Tatarova. Mechanistic basis of panobinostat, venetoclax, and anti-CD40 combination therapy in the immune elimination of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2197.
Colorectal cancer (CRC) progression depends on the close interaction of tumour cells and the tumour microenvironment (TME). Although the TME contributes to poor therapy responses and immune evasion, immune cells within the TME can be therapeutically leveraged, as exemplified by immune checkpoint blockade (ICB). Unfortunately, only a small subset of patients with CRC benefit from ICB therapy; those with immune-activated, microsatellite unstable CRC respond, whereas the predominant group of patients with CRC, those with microsatellite-stable tumours, do not. Although challenging, modulating the TME of CRC to convert these lowly immunogenic and immunosuppressed tumours into immune-activated tumours holds tremendous therapeutic potential. In this Review we provide an overview of the cellular and molecular components of immunity in the TME of CRCs at various stages of disease as well as the mechanisms of immunosuppression and immune evasion. We further describe how systemic and local therapies for CRC impact the tumour and systemic immune microenvironments, and how immunity could serve as a therapeutic and prognostic biomarker. Lastly, we highlight novel immunotherapeutic strategies and approaches that modulate the TME of CRCs to make them amenable to immunotherapy. In this Review, Kennel and Greten highlight the role of immune cells in colorectal cancer (CRC) development, progression and metastasis as well as the impact of therapies on the immune microenvironment. They emphasize the need for novel strategies to enhance immunogenicity and CRC patient stratification to improve outcomes.
Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day−1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95 NCT05735886 . Immune aging fosters multimorbidity and compromises control of infection and cancer. In a phase 1 randomized controlled trial in middle-aged adults, Denk and colleagues administer the mitophagy inducer urolithin A and profile cellular and metabolic aspects of immune aging.
