Chimeric-antigen receptor (CAR)-T cell therapy has shown early promise against glioblastoma, which lacks effective treatment options. However, two key challenges curtail efficacy: tumor-antigen heterogeneity and an immunosuppressive tumor microenvironment. CAR-T cells engineered to secrete combinations of immunomodulatory proteins can reverse immune suppression and engage endogenous immunity. Through head-to-head in vivo comparisons of potentially synergistic armor combinations, we demonstrated that T cells expressing a CAR plus IL-12 and the decoy-resistant form of IL-18 (CAR-12.DR18 T cells) show strong efficacy against antigen-heterogeneous glioma in immunocompetent mice. Robust anti-tumor efficacy with effective toxicity mitigation was achieved via combined administration of CAR-12.DR18 T cells with CAR-T cells that secrete an anti-vascular endothelial growth factor (VEGF-A) single-chain variable fragment. This combination therapy presents a clinically applicable strategy to overcome key barriers to effective treatment of glioblastoma.

Transcriptional intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers. Investigation into the ITH programs that drive tumor metastasis and immune evasion could help identify potential treatment and prevention approaches. Through single-cell RNA sequencing analysis of upper aerodigestive squamous cell carcinoma (UASCC) cells and patient tumors, we uncovered a hybrid epithelial-mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating the STAT1 and CD274 (PD-L1) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, high ETS1 expression in tumors strongly correlated with poor survival and resistance to immune checkpoint blockade (ICB) across multiple cohorts. Drug screening demonstrated that ETS1-high cancers were vulnerable to HSP90 inhibitors (e.g., alvespimycin), which suppress ETS1 by disrupting HIF1α-mediated transcriptional activation. Together, this work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity increases the risk of PDAC through metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese PDAC using genetically engineered mouse models (GEMMs). We hypothesized that KD may also prevent obesity-associated PDAC progression by altering body composition and cancer metabolism. Therefore, male PDAC GEMMs were subjected to diet-induced obesity (DIO) using high-fat diets or maintained on a low-fat diet (LFD) for 15 weeks. Mice were then randomized to continue the initial diets or switch to a KD or matched control diet for 6 weeks. Body weight and composition, glucose tolerance, ketone levels, pancreas histology, and tissue metabolomics were assessed. Furthermore, murine pancreas-derived organoids from DIO or LFD fed GEMMs were treated with a ketone body and analyzed using untargeted metabolomics. In obese PDAC GEMMs, KD delayed cancer progression independent of weight loss, an effect not observed in non-obese LFD-fed mice. KD-mediated PDAC suppression was associated with enrichment of pancreatic metabolic pathways that support non-glucose energy production. Ketone-treated organoids recapitulated a subset of the KD-associated metabolic differences observed in vivo, suggesting a direct metabolic effect on cancer cells. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC. The diet-cancer metabolic interactions highlight potential opportunities for dietary or metabolic interventions to prevent PDAC in high-risk obese populations.

Loss of ARID1A disrupts heterochromatin architecture and induces viral mimicry and immunogenicity in a TRIM28-dependent but SWI/SNF-independent manner, highlighting the potential of targeting the ARID1A-TRIM28 axis to improve immunotherapy efficacy.

Sex differences in tumor immunity are increasingly recognized as important determinants of cancer progression and therapeutic response. In a recent publication, Abdelfattah and colleagues identify a male-biased Yes-associated protein 1 (Yap1)-Cd276 regulatory axis that promotes immune evasion in sonic hedgehog (SHH)-induced medulloblastoma. Although Yap1 regulates tumor immune cell infiltration and immunosuppression in both sexes, disruption of this pathway confers survival benefit only in males, but not females. These findings highlight how oncogenic signaling intersects with tumor immunity and underscore the importance of considering biological sex in studies of cancer immunology and immunotherapy.

Single-cell analyses reveal AKT3-expressing mesenchymal-like cells as drivers of colorectal ovarian metastases, which depends on the dynamic cross-talk between cancer cells and cancer-associated fibroblasts within the immunosuppressive ovarian niche.

Abstract Tumor hypersialylation, overexpression of sialoglycans on cancer cell surfaces, plays a critical role in cancer progression by suppressing both innate and adaptive anti-tumor immunity. Previously, we demonstrated that an untargeted engineered human sialidase enzyme exhibited single agent and T cell-dependent antitumor activity in preclinical tumor models, a favorable safety profile in non-human primates (NHPs) and cancer patients, and proof-of-mechanism of immune modulation and antitumor signals in cancer patients in a clinical trial (NCT05259696). These findings enabled the development of a platform technology in which the engineered human sialidase is fused to tumor-associated antigen (TAA)-targeting antibodies to achieve deeper and longer tumor desialylation, enhancing both antibody-mediated effector cell cytotoxicity (innate immunity) and T-cell-mediated tumor killing (adaptive immunity). Here we report that fusion of the engineered human sialidase to anti-B7-H3 nanobody, designated E-688 (also called HLX316) significantly improves tumor desialylation depth, durability, and efficacy in vitro and in vivo, while maintaining a favorable safety profile. In assays using hypersialylated, B7-H3-expressing cancer cell lines, E-688 demonstrated markedly increased potency and pharmacodynamic (PD) effects compared with the untargeted sialidase, showing > 1,000-fold improvement in desialylation. In vivo, E-688 also exhibited increased durability of desialylation compared with the untargeted sialidase, extending the PD effect in disease models. Furthermore, desialylation of tumor cell surfaces with E-688 was shown to potentiate antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), enhancing antibody-mediated effector cell-killing of tumor cells. Single-agent in vivo efficacy was observed in multiple mouse tumor models. In an A375 humanized mouse model, E-688 was superior to the B7-H3 antibody, untargeted sialidase, and anti-PD-1 antibody. E-688 was also well tolerated with no toxicity findings in a Good Laboratory Practice (GLP) one-month repeat-dose toxicity study in NHPs, with the NOAEL (no observed adverse effect level) determined to be 150 mg/kg. In summary, E-688 represents a first-in-class cancer therapy, a human-sialidase-armed anti-tumor antibody, that desialylates immunosuppressive tumor-surface sialoglycans to enhance innate and adaptive antitumor immunity. By enabling deeper and more sustained tumor desialylation, E-688 enhances antibody-mediated NK- and macrophage- killing of tumor cells and adaptive antitumor immune responses, while maintaining a favorable tolerability profile. Its clinical development is supported by strong in vitro, in vivo, and GLP toxicology data. Citation Format: James Broderick. A First-in-Class Human Sialidase-Armed Anti-B7-H3 Antibody that Enhances Innate and Adaptive Antitumor Immune Responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr ND05.

Altered lipid metabolism is a potential targetable metabolic vulnerability in colorectal cancer (CRC). Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Here, by using samples from a window trial of TVB-2640 treatment in CRC patients, we found that FASN inhibition induced DNA damage but impaired the DNA damage response (DDR). In colon cancer cell lines and patient-derived organoids, FASN inhibition potentiated chemotherapy-induced double-strand DNA breaks (DSBs) and apoptotic cell death by altering histone acetylation levels. In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation. Mechanistically, FASN inhibition attenuated activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to γ-H2AX foci in an acetylation-dependent manner. Moreover, FASN inhibition mediated DNA repair deficiency induced synthetic lethality with PARP inhibition in CRC cells. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.

Immune checkpoint blockade-induced immune-related adverse events (irAEs) hamper the application of this revolutionary anti-tumor therapeutic strategy. Here, we explored the mechanisms driving irAEs by profiling the immune ecosystem of major irAE-affected organs at the single-cell scale. The analysis identified three populations of cytotoxic T lymphocytes that mediate anti-tumor immunity (CTL1) or that induce irAE in the gut (CTLirAE-I) or in multiple other organs (CTLirAE-II). Interleukin-JAK1 signaling was specifically activated in the CTLirAE-II population upon PD-1 blockade. Targeting JAK1 remarkably relieved the irAEs in the heart and lung, without compromising the anti-tumor efficacy. Tracking TCR sequence and transcriptome showed that CTLirAE-II and CTL1 populations originated from lymph node progenitor cells, while the CTLirAE-I population was derived from tissue-resident memory T cells. Moreover, irAEs could be monitored by assessing the CTLirAE-II population in circulation. In conclusion, this study elucidates the landscape of cellular changes in irAEs across multiple organs following immunotherapy and proposes strategies for relieving irAE symptoms and facilitating diagnosis.