Clinical Cancer Research最新文献

Hepatocellular carcinoma (HCC) lacks precise and noninvasive diagnostic tools. To address this, a new positron emission tomography (PET) radiotracer, [68Ga]Ga-XH-06, was developed. It uses an antibody fragment to target glypican-3 (GPC3), a highly specific biomarker, successfully visualizing GPC3 expressions in patients with HCC, potentially meeting an important unmet need. See related article by Lin et al., p. 550.

Monoclonal antibodies (mAb) used in the clinic can engage the immune system through their Fc domains, eliciting effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Although natural killer (NK) cells have historically been implicated as the principal mediators of ADCC, emerging evidence suggests that tumor-associated macrophages (TAM), particularly monocyte-derived subsets, play a central role in ADCP. These macrophages are abundant within the tumor microenvironment, express high levels of activating Fc γ receptors (FcγR), and retain robust phagocytic capacity. However, the heterogeneity of TAMs and the limited understanding of FcγR expression patterns across tumor types have constrained the therapeutic exploitation of ADCP. This review critically examines the contribution of macrophage-mediated ADCP to the activity of both tumor-targeting and immunoregulatory mAbs. We discuss how FcγR polymorphisms, isotype engineering, and antibody effector functions influence therapeutic efficacy, with particular attention to commonly used tumor targeting and immunomodulatory antibodies. The role of inhibitory receptors such as FcγRIIb, CD47, and PD-1 in modulating ADCP is also addressed. Advances in multispecific antibodies targeting tumor antigens alongside ADCP regulators, and preclinical data highlighting the importance of FcγR engagement, underscore the untapped potential of this pathway. We highlight key challenges, including TAM heterogeneity and macrophage hypophagia. Emerging strategies integrating synthetic biology and FcγR profiling may enable the rational design of therapies that selectively enhance ADCP. Macrophage-mediated ADCP represents a promising but underexploited axis in cancer immunotherapy, warranting further mechanistic investigation and translational development.

On December 4, 2025, the American Association for Cancer Research (AACR) released its inaugural AACR Pediatric Cancer Progress Report, which highlights the remarkable scientific and clinical advances transforming outcomes for children (ages 0-14) and adolescents (ages 15-19) with cancer. This first-of-its-kind report encompasses progress against pediatric cancers made over the past decade and chronicles major developments in molecularly targeted therapies, immunotherapies, and genomic profiling that are reshaping pediatric cancer diagnosis, surveillance, and treatment. The report also underscores the enduring challenges that impede progress, including the lack of effective therapies for rarer and aggressive pediatric cancers and the persistent inequities in access to high-quality treatment and supportive care, both in the United States and worldwide. Collectively, these insights reaffirm the urgent need for increased federal investment, strengthened international collaboration, and innovative research strategies to accelerate progress against pediatric cancer. The full report is freely available at PediatricCancerProgressReport.org.

Purpose: Human papillomavirus (HPV) integration (HPVint) is associated with carcinogenesis and tumor progression in HPV-associated cancers, including head and neck squamous cell carcinomas (HNSCC). Although its impact on human DNA has been well characterized, its relationship with clinical outcomes remains unconfirmed.

Experimental design: We analyzed HPVint events from 261 HPV-associated HNSCC bulk and single-cell RNA sequencing (scRNA-seq) samples from five cohorts, including 62 from a new University of Michigan cohort, and DNA HPVint events from 102 HPV(+) HNSCC participants in two of the cohorts. We investigated the consequences of HPVint both with respect to human and HPV gene expression and clinical outcomes (recurrence and overall survival).

Results: By leveraging this large meta-cohort of HNSCC, we first reveal an oncogenic gene network based on the recurrent HPVint locations in the human genome and gene expression alterations, highlighting key recurrent and overexpressed genes, including NR4A2, CD274, and CCER1, and genes from the CAMK and KLF families. We then stratify HPVint-positive participants by risk using HPV RNA features, specifically spliced HPV-human fusion transcripts (E1* integration) and HPV gene expression ratios, showing that subsets of participants have worse clinical outcomes based on these two candidate biomarkers.

Conclusions: By focusing on RNA instead of DNA, we expand our understanding of the carcinogenic mechanisms of HPVint, in part addressing the conflicting findings of whether HPVint is associated with aggressive phenotypes and worse clinical consequences, and provide potential biomarkers to advance precision oncology in HPV-associated HNSCC. Newly identified genes with recurrent integration events may serve as candidates for targeted therapy.