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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.

Cancer stem cells (CSCs) shape immunosuppressive tumor microenvironments through diverse mechanisms. In this issue of Cancer Cell, Fan et al. demonstrate that CSC-derived extracellular vesicles promote regulatory T cell expansion and facilitate immune evasion. The mechanistic details reveal a therapeutic vulnerability that enhances responses to checkpoint blockade.

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.

Hayward et al. show that stromal fibrosis drives epithelial STAT3-mediated chemokines to recruit macrophages. Macrophages respond to elevated tissue tension by undergoing lipid peroxidation, generating aldehydes that induce epithelial DNA damage and promote tumor progression. This study connects fibrosis and inflammation to DNA damage in cancer risk and progression.

Despite progress in elucidating the molecular landscape and actionable vulnerabilities of cholangiocarcinoma, clinical outcomes for patients with advanced disease remain dismal. In this issue of Cancer Cell, Entrialgo-Cadierno et al. raise the bar for the ∼20%–25% of patients with oncogenic KRAS mutations by unlocking the therapeutic potential of direct RAS-GTP inhibition.

In this issue of Cancer Cell, Hayward et al. show that fibrotic tissue tension creates a mechanically organized mutagenic niche. A stiff stroma activates epithelial STAT3, recruits macrophages, and drives NOX-dependent lipid peroxidation, generating diffusible aldehydes that damage epithelial DNA in fibrotic tumors and mammographically dense breast tissue.

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.

Tumor cells evade anti-tumor immunity by reprogramming TME. Fan et al. uncover that cancer stem cells of TNBC drive regulatory T cells differentiation and expansion via a paracrine signaling mediated by TSPAN8-enriched extracellular vesicles (EVs), independent of canonical EV cargo internalization. Neutralizing EVs-TSPAN8+ enhances anti-PD-1 efficacy in TNBC preclinical models.

Zhuo et al. identify a conserved cutaneous re-epithelialization program, MP10 that underlies pancreatic cancer malignancy. Distinct from EMT, this program is driven by the transcription factor FOSL1 during the transition from precursor lesions. Wound-like CTHRC1high myCAFs promote FOSL1 expression through EGFR signaling, revealing targetable tumor-stroma crosstalk in PDAC progression.

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.