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 the important unmet need.

Monoclonal antibodies (mAbs) 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). While natural killer (NK) cells have historically been implicated as the principal mediators of ADCC, emerging evidence suggests that tumour-associated macrophages (TAMs), particularly monocyte-derived subsets, play a central role in ADCP. These macrophages are abundant within the tumour microenvironment, express high levels of activating Fc gamma receptors (FcγRs), and retain robust phagocytic capacity. However, the heterogeneity of TAMs and the limited understanding of FcγR expression patterns across tumour types have constrained the therapeutic exploitation of ADCP. This review critically examines the contribution of macrophage-mediated ADCP to the activity of both tumour-targeting and immune-regulatory mAbs. We discuss how FcγR polymorphisms, isotype engineering, and antibody effector functions influence therapeutic efficacy, with particular attention to commonly used tumour 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 tumour 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.

Purpose: Liposarcoma is the most common soft tissue sarcoma. Well-differentiated liposarcoma can progress to dedifferentiated liposarcoma (DDLPS), a more aggressive form with higher metastatic potential and poor response to existing therapies. Progress in understanding and treating liposarcoma has been limited. To address this, we sought to develop an immunocompetent genetically engineered mouse model of liposarcoma.

Experimental design: We developed an autochthonous, immunocompetent liposarcoma mouse model [AAV8-Ap2.2-eGFP/Cre Ptenf/f;Trp53f/f C57BL/6 (ACPP)] by using targeted Cre-mediated deletion of Trp53 and Pten in adipocytes to mimic the signaling alterations observed in human liposarcoma. We characterized the histology, transcriptional features, and tumor microenvironment of this model. Additionally, we established syngeneic cell lines derived from ACPP DDLPS tumors and evaluated them for tumor formation, growth dynamics, and immune composition after implantation.

Results: ACPP mice develop well-differentiated liposarcoma, DDLPS, and mixed tumors, mirroring human disease. Both murine and human DDLPS tumors share key transcriptional features and exhibit heterogeneous T-cell infiltration. Syngeneic DDLPS cell lines reliably form tumors in vivo, with each line demonstrating distinct growth kinetics, aggressiveness, and immune profiles.

Conclusions: The ACPP model provides a novel and clinically relevant platform to study liposarcoma in an immunocompetent setting. Along with the ACPP-derived cell lines, these models not only provide essential tools to understand the complex immunobiology of liposarcoma but also can be used to elucidate the underlying molecular mechanisms driving liposarcoma generation and progression and significantly accelerate the pace of preclinical studies aimed at uncovering more effective new therapies for patients with this aggressive malignancy.