BackgroundThird‐generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show initial efficacy in EGFR‐mutated lung cancer, but residual disease persists. This study aimed to investigate cluster of differentiation 24 (CD24) as a translational immunotherapeutic target for enhancing third‐generation EGFR‐TKI efficacy.MethodsWe conducted RNA‐sequencing (RNA‐seq) on drug‐responsive, drug‐tolerant persister, and drug‐resistant cells to identify therapeutic targets to pair with EGFR‐TKIs. For validation, we integrated single‐cell RNA‐seq data from 29 lung cancer specimens and used single‐nucleus RNA‐seq and immunohistochemistry on clinical residual tumor samples following TKI therapy (TKI‐residual). With CRISPR/Cas9, we studied the effect of CD24 on proliferation and phagocytic clearance during EGFR‐TKI treatment. We tested CD24 knockout or ATG‐031 (a first‐in‐class CD24 antibody) with EGFR‐TKIs in vitro, xenografts, and spontaneous lung cancer models. To explore mechanisms, we used DNA affinity precipitation, chromatin immunoprecipitation sequencing, and luciferase assays to identify transcription factors regulating CD24. Co‐immunoprecipitation combined with mass spectrometry and phosphoproteomics were used to study YIN‐YANG‐1 (YY1) S247 phosphorylation's expression and function, while kinase inhibitors assessed upstream phosphorylation of YY1 S247 and its regulation of CD24.ResultsCD24 expression rose in drug‐responsive, ‐resistant, and ‐tolerant lung cancer cells and post‐EGFR‐TKI treatment clinical specimens. This elevation promoted cell proliferation and shielded tumor cells from macrophage‐mediated phagocytosis. Genetic depletion of CD24 or treatment with ATG‐031 significantly enhanced phagocytosis and tumor eradication in vitro, in xenografts, and in mice harboring EGFRL858R·T790M‐driven spontaneous lung tumors. Furthermore, we revealed that YY1 S247 phosphorylation was responsible for the upregulation of CD24 upon EGFR‐TKI treatment, facilitating YY1 dimerization and the formation of promoter‐enhancer loops that regulate CD24 expression.ConclusionsCD24 is a promising target in EGFR‐mutated lung cancers, potentially enhancing efficacy of third‐generation EGFR‐TKIs.

Cancer immune checkpoint inhibitors (ICIs) have brought breakthroughs, but only about one‐third of cancer patients benefit from ICIs. In recent years, targeting non‐apoptotic regulated cell death (RCD) subtypes, such as ferroptosis, necroptosis, autophagy, cuproptosis, and pyroptosis, has emerged as a novel strategy in cancer therapy due to their ability to release damage‐associated molecular patterns (DAMPs), enhance antigen presentation, and remodel the tumor immune microenvironment, thereby activating anti‐tumor immune responses. A number of studies have shown that precise induction of these pathways by small molecules or nanoparticles can reverse the resistance to chemoradiotherapy and ICIs, promote the transformation of “cold tumors” to “hot tumors,” and ultimately establish durable immune memory. This article systematically reviewed the key mechanisms and immunomodulatory functions of five types of non‐apoptotic RCD (ferroptosis, necroptosis, autophagy, cuproptosis, and pyroptosis), discussed the related treatment strategies, and prospects for the future application in combination with existing immunotherapy.

Radiopharmaceuticals are reshaping the landscape of cancer therapy, offering a unique theranostic advantage that is becoming increasingly central to precision medicine. By labeling the same molecular scaffold with different radionuclides, these agents enable seamless integration of diagnostic imaging and targeted therapy. Clinical breakthroughs with somatostatin receptor subtype 2 (SSTR2)‐ and prostate‐specific membrane antigen (PSMA)‐targeted radiopharmaceuticals have significantly enhanced both tumor visualization and therapeutic efficacy, establishing new benchmarks in oncology. Ongoing research is exploring novel molecular targets such as cholecystokinin‐2 receptor (CCK2R), fibroblast activation protein (FAP), and C‐X‐C chemokine receptor type 4 (CXCR4). In parallel, there is growing interest in utilizing alternative radionuclides, including alpha‐particle emitters and Auger electron emitters, beyond the commonly used beta‐emitters, to improve therapeutic outcomes. Simultaneously, advances in ligand and linker design are being leveraged to optimize in vivo pharmacokinetics and tissue distribution. Among the emerging targets, CCK2R has attracted notable attention due to its overexpression in multiple malignancies. Research efforts have focused on improving ligand stability, receptor‐binding affinity, and tumor retention, while also exploring strategies to enhance CCK2R expression on cancer cells. This review offers a comprehensive overview of the current landscape in cancer radiotheranostics, exploring the role of CCK2R in cancer biology and summarizing the latest advancements in the development of CCK2R‐targeted radiopharmaceuticals. Using these advancements as a case study, we systematically examine key aspects of next‐generation radiopharmaceutical design, from target selection and ligand engineering to pharmacokinetic optimization and clinical translation, providing a multidimensional framework for future innovation in cancer radiotheranostics.

BackgroundHormone receptor‐positive (HR+)/humaal growth factor receptor 2‐negative (HER2‐) breast cancer, the most common breast cancer type, has variable prognosis and high recurrence risk. Neoadjuvant therapy is recommended for median‐high risk HR+/HER2‐ patients. This phase II, single‐arm, prospective study aimed to explore appropriate neoadjuvant treatment strategies for HR+/HER2‐ breast cancer patients.MethodsEligible female patients with newly diagnosed, untreated HR+/HER2‐ breast cancer received 2 cycles of nab‐paclitaxel and carboplatin (nabPCb). Magnetic resonance imaging (MRI) was performed to assess tumor responses, and ≥40% regression of the maximal tumor diameter was deemed chemo‐sensitive. Chemo‐sensitive patients continued nabPCb for 4 more cycles (group A). Chemo‐insensitive patients were randomized to groups B, C, and D at a ratio of 1:3:1 to receive a new chemotherapy for 4 cycles or endocrine‐immune‐based therapy (dalpiciclib, letrozole and adebrelimab, with goserelin if patients were premenopausal) for 4 cycles or to undergo surgery. Peripheral blood and core‐needle biopsy (CNB) samples were collected before treatment, followed by a next‐generation sequencing (NGS) panel detection and similarity network fusion (SNF) typing through digital pathology data. The primary endpoint was the pathological complete response (pCR) rate, and the secondary endpoint was the clinical objective response rate (ORR).ResultsA total of 121 patients were enrolled (67.8% with stage III disease), with 76, 9, 27, and 9 patients in groups A, B, C and D, respectively. The total pCR rate was 4.1%, and all patients who received pCR were in group A. Group C had a better ORR than Group B (81.5% vs. 66.7%). Exploratory analysis revealed that patients with the SNF4 subtype were the most sensitive to nabPCb (pCR rate of 21.1% vs. 1.8% in group A), whereas patients in group C with the SNF2 subtype were more sensitive to endocrine‐immune‐based therapy (Miller‐Payne grade 4‐5, 45.5% vs. 6.3%).ConclusionsConverting to endocrine‐immune‐based therapy improved the ORR, but not the pCR rate in chemo‐insensitive patients. Neoadjuvant chemotherapy and endocrine therapy are not mutually exclusive. The SNF4 subtype of HR+/HER2‐ breast cancer was more chemo‐sensitive, whereas the SNF2 subtype might be more sensitive to immunotherapy.