ArchiveEarly colorectal cancer is often treated through endoscopic procedures to remove tumors. However, when initial removal is incomplete or shows high-risk features, further major surgery is required to ensure no cancer remains. This consensus provides a standard for surgeons to decide when and how to perform this additional surgery. A multidisciplinary group of Chinese medical experts reviewed global research and clinical evidence published between 2010 and 2024. The medical experts formulated key clinical recommendations, which were then discussed and finalized through expert voting to ensure high agreement. The consensus identifies specific high-risk factors necessitating additional surgery. The consensus recommends that these follow-up surgeries should ideally take place approximately 4 weeks after the first procedure. Furthermore, the consensus provides detailed protocols for marking the tumor location and selecting the best surgical approach. These consensuses offer a practical framework to improve the safety and effectiveness of treating early colorectal cancer. By standardizing surgical decisions, the consensus aims to help patients achieve better long-term recovery and quality of life.
Tumor-associated macrophages (TAMs), essential components of the tumor immune microenvironment (TIME), undergo metabolic reprogramming as part of functional adaptation. Tumor cells modulate TAMs through multiple mechanisms, including metabolic cross-feeding, cytokine production, extracellular vesicles, tumor-derived proteins (such as GRP78) and pathogen-associated patterns (such as Lipopolysaccharide) signaling mediators. In turn, metabolic alterations in TAMs fine-tune TAM function via intricate signaling networks with outcomes that vary across cancer types. These functional and phenotypic shifts enable TAMs to influence malignant cells and other TIME components, such as T cells, NK cells, and fibroblasts, through the secretion of inflammatory factors and changes in surface marker expression. This process establishes an extensive network of interconnected cellular crosstalk. In this review the metabolic alterations-intracellular signaling-TAM biology axis is linked to cancer progression contributions and the implications for immunotherapy across diverse malignancies. Building on these insights, current preclinical and clinical studies with a focus on TAMs were surveyed and the advantages and challenges of TAM-targeted therapeutic strategies were systematically evaluated. We anticipate that these perspectives will spur further investigation into TAM-specific immune targets and accelerate the development of next-generation cancer immunotherapies.
Antibody-drug conjugates (ADCs) have emerged as a transformative class of cancer therapeutics by combining the target precision of antibodies with the potent cytotoxic effects of chemotherapeutic agents. This unique approach aims to enhance the effectiveness of cancer treatment while minimizing systemic toxicity. This review provides a comprehensive overview of ADC development, starting with explorations of the structural and mechanistic foundations, and advancing to in-depth analyses of ADCs that have achieved clinical success. Despite remarkable progress, the development of drug resistance remains a significant barrier to broader clinical application. We discuss the mechanisms underlying resistance, including alterations in target antigens, disruptions in ADC internalization, and dysfunctions of intracellular trafficking. To address these challenges, we propose several strategies, such as designing next-generation ADCs equipped with improved linkers and novel payloads, implementation of combination therapies, and simultaneous targeting of multiple pathways to circumvent resistance. In conclusion, this review highlights the critical need for innovative approaches in the evolving ADC landscape, aiming to overcome resistance mechanisms and fully harness the therapeutic promise of ADCs in cancer treatment.
The integration of immune checkpoint inhibitors has transformed the therapeutic landscape for patients with resectable and potentially resectable stage III non-small cell lung cancer, providing unprecedented opportunities for curative treatment. Several trials have investigated immune checkpoint inhibitors, either alone or in combination with chemotherapy or radiotherapy, as neoadjuvant and/or adjuvant approaches for resectable and potentially resectable stage III non-small cell lung cancer. This comprehensive review elaborates and deeply analyzes the evolving evidence from landmark clinical trials and emerging treatment strategies. Despite these promising outcomes, significant challenges remain, including optimal treatment modality selection, controversy about adjuvant immunotherapy for patients who have already achieved a pathologic complete response, appropriate endpoint evaluation, and biomarker identification. This review also discusses future directions for optimizing immunotherapy integration in patients with resectable stage III non-small cell lung cancer, emphasizing the need for personalized treatment approaches to maximize patient benefit while addressing unanswered clinical questions.
Hepatitis B virus (HBV) is the primary driver of liver cancer (LC), a malignancy characterized by extensive metabolic reprogramming. However, the specific mechanisms linking viral oncoproteins to metabolic dysregulation in LC remain incompletely understood. This study was aimed at investigating the function of the metabolic enzyme GPT2 in hepatocarcinogenesis, focusing on its regulation by HBV X protein (HBx) and its effects on downstream signaling pathways.
We combined analysis of multiple patient cohorts with in vitro and in vivo functional assays to determine the clinical relevance and function of GPT2. Co-immunoprecipitation, ubiquitination assays, and targeted pharmacological or genetic manipulations were used to delineate the signaling cascade.
GPT2 was significantly downregulated in LC, and its low expression correlated with poor patient survival. Functionally, GPT2 loss promoted LC cell proliferation, migration, and lipid accumulation. Mechanistically, GPT2 was found to suppress the mTOR pathway by disrupting the AKT–mTOR interaction and leading to upregulation of ADH1A. In turn, ADH1A facilitates CBL-mediated ubiquitination and degradation of LSD1, a key driver of lipogenesis. Critically, the HBV oncoprotein HBx functions as a molecular adaptor that recruits TRIM25 to GPT2, thus leading to GPT2 ubiquitination and proteasomal degradation. Moreover, HBx-mediated loss of GPT2 was found to drive tumor progression by modulating the mTOR–ADH1A–LSD1 axis and enhancing lipid synthesis.
Our study delineated a novel HBx–TRIM25–GPT2–ADH1A–LSD1 signaling axis promoting virus-associated hepatocarcinogenesis. GPT2 was identified as a critical metabolic tumor suppressor hijacked by HBV and a promising therapeutic target for treating HBV-associated LC.
Conventional tumor-infiltrating lymphocyte (TIL) therapy for solid tumors relies on high-dose interleukin-2 (IL-2) during expansion and post-infusion, and promotes T-cell exhaustion and toxicity. Herein, we developed a feeder-free, low-dose IL-2 TIL expansion protocol and evaluated whether hydroxychloroquine (HCQ) or programmed cell death protein 1 (PD-1) blockade might enhance therapeutic efficacy and decrease IL-2 dependence.
TILs from multiple solid tumors were expanded ex vivo with decreased-dose IL-2, IL-7, and IL-15 plus CD3/CD28 co-stimulation, without feeder cells. TIL products were assessed via quality control, T-cell phenotypes, and exhaustion markers. Cytotoxic activity was measured in vitro through interferon-gamma (IFN-γ) release and real-time cell analysis (RTCA). HCQ-induced changes in major histocompatibility complex class I (MHC-I) and programmed death-ligand 1 (PD-L1) expression were assessed in tumor cell lines, and RTCA-based cytotoxicity was evaluated using T-cell receptor–engineered T cells (TCR-T cells). The in vivo efficacy of HCQ and PD-1 blockade separately combined with TIL therapy was examined in a colorectal cancer patient-derived xenograft (PDX) model.
The protocol consistently produced viable TILs of favorable quality across tumor types, with variable CD8+ and memory T-cell profiles. Expanded TILs showed effector-to-target (E:T) ratio-dependent tumor cell killing in RTCA and secreted IFN-γ across multiple tumor types. HCQ significantly upregulated MHC-I expression in vitro (P < 0.05) without affecting PD-L1 expression or impairing TIL proliferation, and enhanced early TCR-T–mediated killing. In the PDX model, TIL plus HCQ, compared with TIL, showed less tumor growth and greater MHC-I expression, although these differences were not significant, given the small sample size. TIL plus low-dose PD-1 blockade significantly reduced tumor volume versus the control group (P = 0.002) and maintained higher body weights than the TIL-only and control groups.
The feasibility of a feeder-free, low-dose IL-2 TIL expansion system was demonstrated. PD-1 blockade significantly enhanced antitumor activity and treatment tolerability, thus supporting its promise as an alternative to high-dose IL-2. HCQ demonstrated potential immunomodulatory effects, although its in vivo benefit was minimal. This strategy warrants further clinical evaluation in solid tumors.
The cancer-immunity cycle (CIC) outlines key steps of anti-tumor immunity from antigen release to T cell effector function. A comprehensive evaluation of the CIC in patients with breast cancer is lacking, which limits the accurate assessment of immune status and selection of patients suitable for immune checkpoint inhibitor (ICI) therapy.
A signature that describes the six steps of the CIC in the primary tumor was constructed. This signature was used to calculate a CIC score in our previously published breast cancer cohort (n = 752) and classify patients into 3 distinct CIC clusters. The predictive value of the ICI response was validated in pan-cancer ICI-treated cohorts. Clusters with distinct characteristics were further identified through multi-omic analyses, including genomics, metabolomics, and single-cell RNA sequencing.
Breast cancer patients were classified into three CIC clusters: cluster 1 [C1] (immune-cold); cluster 2 [C2] (antigen presentation-deficient); and cluster 3 [C3] (immune-hot). C3 showed abundant immune infiltration that correlated with a better ICI response. In addition to reduced immune infiltration, C1 patients exhibited macrophage phenotypic conversion. The tumor microenvironment of C2 was marked by elevated regulatory T cells and dysfunctional dendritic cells. Genomic analysis of C2 showed a high tumor mutational burden with frequent HLA loss of heterozygosity. C1 was enriched in lipid metabolism pathways and C3 in glycolysis features. PSAT1, a serine-related gene, was identified as a key metabolic regulator in C2, suggesting a role in influencing immunoregulatory molecules.
This study provided a novel framework for classifying tumors based on the CIC characteristics, revealing distinct biological and clinical profiles and suggesting broad clinical significance.
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