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In a recent Nature article, Koeber et al. engineer synthetic super-enhancers from glioblastoma-specific regulatory circuitry to act as precise gene switches. Combined with viral delivery of cytotoxic and immune-stimulating payloads, this approach activates therapy selectively in tumor cells, enabling targeted tumor clearance and durable immune memory.

Resistance to antibody drug conjugates (ADCs) may be due to low target antigen expression resulting in reduced intracellular payload concentration. In this issue of Cancer Cell, Wang et al. show that increased target antigen NECTIN4 expression is associated with reduced NECTIN4-ADC internalization and enhanced extracellular ADC release in a resistant tumor cell subpopulation.

Enfortumab vedotin, a NECTIN4-targeting antibody-drug conjugate (ADC), is in clinical use for urothelial cancer. Using patient specimens and preclinical models, Wang et al. identify an endocytic trafficking defect that limits ADC uptake and efficacy and propose a strategy to overcome this resistance. This trafficking-based mechanism may also underlie resistance to other ADCs in the clinic.

Human epidermal growth factor receptor 2 (HER2, encoded by ERBB2) is an oncogenic driver in multiple cancers. Beyond canonical signaling, HER2 remodels the tumor microenvironment by suppressing antigen presentation, enhancing checkpoint expression, and driving cytokine-mediated suppression. This remodeling creates an immune-resistant environment, posing a barrier to sustained tumor control. Improving efficacy of HER2-targeted strategies will revolve around these immunomodulatory features. Here, we discuss strategies to maximize the potential of HER2 targeting, with a focus on addressing HER2-driven immunomodulation.

In Nature, Buissant des Amorie et al. demonstrate that colorectal cancer acquires oncofetal cell states that resemble embryonic intestines, confer stem-like features, reshape epithelial identity, and prime cells for invasion and metastasis. Oncofetal cells are essential for metastasis and ubiquitous in non-metastatic tumors, with cancer-associated fibroblasts as key microenvironmental drivers.

In this issue of Cancer Cell, Alonso et al. demonstrate that in patients with advanced colorectal cancer, there are regionally distinct genomic and transcriptomic adaptive responses to KRAS G12C inhibition, including epithelial cell state changes and pro-inflammatory pathway enrichment, and provide insights into key resistance mechanisms to KRAS G12C inhibition.

Pancreatic ductal adenocarcinomas (PDACs) are lethal cancers resistant to immunotherapies. In this issue of Cancer Cell, Kureshi et al. show that combining checkpoint blockade with STING-mediated innate immune stimulation unlocks cDC2-driven CD4+ T cell immunity in mice, promoting PDAC immune control. This cellular axis may be exploited for PDAC therapy.

In this review, Pistilli et al. examine persistent challenges in antibody-drug conjugate (ADC) development, including patient selection, biomarker validation, and preclinical modeling. Integrating emerging insights into tumor biology, resistance, and microenvironmental effects, the authors propose reframing ADCs as tumor-ecosystem-targeting therapies and outline paths to embed ADCs within precision oncology.

Liang et al. reveal that TREM2+ LAMs recycle fatty acids through efferocytosis to support tumor adaptation to immune-checkpoint blockade. The fatty acid-containing extracellular vesicles fuel acetyl-CoA-dependent H3K36 acetylation to activate MYC and TGF-β programs. Genetic or pharmacologic TREM2 inhibition restores therapeutic sensitivity through epigenetic remodeling of immunosuppressive tumor microenvironment.

Tang et al. establish a cell-type-resolved prognostic atlas for pancreatic cancer by integrating single-nucleus transcriptomes with long-term survival data from 152 patients. By bridging intra-tumoral gene expression with patient survival, this work establishes a framework for prognostic research, advancing the field from bulk-level analyses to cell type-specific resolution.