Deciphering the molecular and cellular mechanisms underlying the progression of early-stage lung adenocarcinoma (LUAD) is critical for advancing early detection and therapeutic strategies. This study aims to map the evolutionary trajectory from precursor lesions to invasive adenocarcinoma. We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic analyses to evaluate LUAD progression across four histologic stages:atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). Findings were further validated using a stage-specific A/J mouse model to confirm functional cellular interactions. We identified a tumor-intrinsic program characterized by elevated SRGN expression that is associated with Epithelial–Mesenchymal Transition (EMT) and cell proliferation, intensifying as the disease progresses. In parallel, a stage-dependent accumulation of C1QC+ macrophages was observed. Spatial colocalization analysis revealed that SRGN+ malignant cells and C1QC+ macrophages are closely positioned within the tumor microenvironment. We detected progressively enhanced interactions between SRGN+ malignant cells and both exhausted T cells and C1QC+ macrophages, mediated by specific receptor-ligand pairs, including MIF–LIFR, ADAM17–ERBB4, OSM–EGFR, and OSM–TNFRSF14. The A/J mouse models confirmed the co-emergence and functional cooperation of these populations. Our findings highlight a coordinated epithelial-macrophage module that drives LUAD progression. The identification of SRGN and its associated spatial interactions offers potential molecular targets for early therapeutic intervention and diagnostic modeling.

Yippee-like 3 (YPEL3) has been implicated in the regulation of apoptosis, proliferation, and invasion in various cancers, but its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we integrated pan-cancer data, TCGA/GEO transcriptomes, DNA methylation profiles, and single-cell RNA sequencing to explore YPEL3's expression, prognosis, and immune relevance in HNSCC. YPEL3 was downregulated in tumor tissues and correlated with better overall survival, particularly in advanced-stage patients. Functional assays confirmed that YPEL3 suppressed proliferation, migration, and invasion while promoting apoptosis in vitro; its knockdown accelerated tumor growth in vivo. Bulk transcriptomics and TIMER analysis revealed that high YPEL3 expression was associated with increased stromal and immune infiltration, including CD8+ T cells. Single-cell analysis identified an epithelial subcluster (Epi.C3) enriched for YPEL3, expanded in tumors, and linked to poor prognosis. Mechanistically, YPEL3-high epithelial cells secreted CXCL16, interacting with CXCR6 on CD8+ T cells to promote immune engagement. YPEL3 regulated CXCL16 via CREB1 but not TFAP2C. Co-culture assays showed that epithelial YPEL3 modulated the CXCL16-CXCR6 axis in T cells. In vivo, YPEL3 loss was associated with reduced CD8+ T-cell infiltration and impaired CD8+ T-cell effector function, as indicated by decreased Granzyme B, Perforin, IFN-γ, and TNF-α. Together, these findings identify YPEL3 as a tumor suppressor and an important mediator of epithelial-immune crosstalk in HNSCC, linking epithelial differentiation-associated states to antitumor immunity through the CREB1/CXCL16/CXCR6 axis.

Background:Early identification of Pre-chronic obstructive pulmonary disease (pre-COPD) is vital for preventing irreversible lung damage. However, despite its high prevalence, there is a lack of practical tools to predict which individuals will progress to spirometry-defined COPD. This study aimed to identify independent risk factors and develop a clinical nomogram to quantify the risk of disease progression in a pre-COPD population. Methods:We conducted a multicenter, retrospective cohort study in Southwest China (2019-2023), enrolling 1088 participants with pre-COPD. Baseline data, including demographic information, smoking status, comorbidities, lung function, and hematological and biochemical indicators, were analyzed. Independent predictors were identified via multivariate logistic regression, and a risk-prediction nomogram was constructed and validated. Results:During follow-up, 54.6% of participants progressed to COPD. The final prediction model identified six independent risk factors: age (OR=1.043), hypertension (OR=2.331), diabetes (OR=2.412), hemoglobin level (OR=1.016), lymphocyte count (OR=0.639), and basophil count (OR=1.411). The nomogram demonstrated robust discriminative ability, with an AUC of 0.758 in the training set and 0.718 in the validation set. Calibration curves showed high consistency, and Decision Curve Analysis (DCA) confirmed significant clinical net benefit. Conclusion:Progression from pre-COPD to spirometry-defined COPD is highly prevalent and driven by age, comorbidities, and systemic inflammatory markers. Our validated nomogram provides a precise, non-invasive tool for clinicians to identify high-risk individuals, enabling targeted early intervention and optimized resource allocation in COPD prevention.

Severe respiratory infections have imposed an immense burden on healthcare worldwide, which could lead to fatal outcomes. The dysfunctional immune response impacts disease severity of respiratory infections, yet its underlying mechanisms remain largely obscure. We explored the immunologic response underpinning severe respiratory viral infections by performing single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from 17 patients with coronavirus disease 2019 (COVID-19), including moderate, severe, critical, and convalescent cases. Furthermore, we analyzed the host responses following low- or high-dose vaccination with recombinant protein. We constructed an immunocyte landscape with 299,527 PBMCs. The significant dysregulation of immune homeostasis in severe respiratory viral infections was characterized by an increased ratio of CD14+ monocytes and exhausted CD8+ T cells, and reduced Tregs, memory T cells and cDC2 cells. Notably, highly inflamed CD14+ monocytes overexpressing interleukin (IL)-related genes emerged as central contributor of inflammatory storms in critical patients. Enhanced inflammatory response in exhausted CD8+ T cells, FOS/JUN overexpression in Tregs and Th17 cells, as well as suppressed antigen presentation activity in cDC2 cells were also remarkable features of severe and critical cases. Moreover, the high-dose vaccination with recombinant protein inhibited the inflammatory response of CD14+ monocytes, while enriched the memory T/NK cells to boost protective immunity. In mechanism, activated IL-6-JAK-STAT in CD14+ monocytes and T cells, coupled with impaired interferon (IFN)-α pathway, could drive excessive inflammatory response. Our study creates a high-resolution transcriptomic atlas that uncovers distinct immune signatures across the disease severity of respiratory infections, which provides valuable resource for mechanistic exploration and therapeutic strategies development. Furthermore, we demonstrate that high-dose recombinant protein vaccines might mitigate the severity of illness. This study was prospectively registered at ChiCTR (Registration number: ChiCTR2300067787).

Small nucleolar RNAs (snoRNAs) play crucial regulatory roles in various cancers. However, the mechanisms by which snoRNAs regulate N6-methyladenosine (m6A) modifications in colorectal cancer (CRC) remain unclear. This study systematically deciphered the precise interaction mechanism between SNORD78 and the m6A reader IMP2 in CRC. We demonstrate that SNORD78 specifically stabilizes IMP2 to activate the PIK3CD-CHKA-Kennedy pathway in an m6A-dependent manner, promoting endoplasmic reticulum stress (ERS) and phosphatidylcholine (PC) biosynthesis, thereby driving CRC. Conversely, the SNORD78-targeting antisense oligonucleotide (ASO), ASO-78, effectively suppresses ERS and PC levels, inhibiting CRC progression. Mechanistically, SNORD78, relying on the "UAAUGA" element in its C-D box region, specifically binds to the Lys221 ubiquitination site of IMP2, blocking TRIM25-mediated degradation of IMP2 and maintaining its stability. IMP2 enhanced the stability and translation of the target mRNAs PIK3CD and CHKA by recognizing their corresponding m6A positions, m6A-3208 and m6A-1619, respectively, to reshape the phosphatidylcholine metabolite profile in CRC cells. In terms of potential therapeutic strategies, the ASO-78 can significantly inhibit CRC cell proliferation, reduce ERS levels, and decrease phosphatidylcholine content. The combination of ASO-78 and IMP2 inhibitor IMP2-IN1, by dual blocking of the SNORD78-IMP2 axis, exhibits an excellent proliferation-inhibiting effect in CRC organoids. This study not only reveals a mechanism by which the SNORD78-IMP2 interaction regulates CRC occurrence and development but also provides theoretical basis for innovative therapeutic strategies for precise targeting of tumor snoRNA-m6A reader interactions.

IL‑6, a pleiotropic inflammatory cytokine predominantly secreted by fibroblasts, myeloid‑derived suppressor cells, tumor‑associated macrophages and tumor cells, is associated with poor prognosis of and therapeutic resistance in non‑small cell lung cancer (NSCLC). The activation of signaling pathways, including the JAK/STAT3, MAPK and PI3K/AKT pathways, promotes tumor survival. Furthermore, the IL‑6/JAK/STAT3 signaling axis has emerged as a key driver of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKI) resistance, orchestrating intricate crosstalk within the tumor microenvironment (TME) to promote cell survival and immunosuppression. The present review synthesized current evidence on the dual role of IL‑6 in mediating EGFR‑TKI resistance and blunting anti‑tumor immunity. The present review highlights the preclinical rationale for combining IL‑6 blockade with EGFR‑TKI or immune checkpoint inhibitors to overcome refractory disease. The present review also highlights the structure, molecular mechanisms and clinical insights of IL‑6 in the TME of EGFR‑mutant NSCLC and may provide optimized therapeutic strategies for EGFR‑TKI‑refractory NSCLC.

OBJECTIVES:To determine whether prognosis after neoadjuvant chemo-immunotherapy is better predicted by pretreatment clinical nodal stage or post-treatment pathological nodal status, and whether patients downstaged to ypN0 have outcomes comparable to those with primary N0. METHODS:We conducted a multicenter retrospective cohort study of patients with resectable NSCLC treated with neoadjuvant chemo-immunotherapy followed by curative-intent surgery between January 2020 and December 2024. Patients were categorized as Natural N0 (cN0/ypN0), Downstaged N0 (cN+/ypN0), or ypN + according to baseline clinical and postoperative pathological nodal status. RFS and OS were analyzed using Kaplan-Meier and Cox regression methods. Subgroup analyses were performed in ypN0 patients to assess the association of adjuvant immunotherapy with survival. RESULTS:A total of 413 patients were included, and 207 (67.0%) with clinical nodal metastasis achieved nodal downstaging to ypN0. The overall MPR and pCR rates were 62.5% and 35.8%, respectively. After a median follow-up of 29.2 months, 2-year RFS and OS rates were 78.0% and 93.3%. Downstaged N0 had survival comparable to Natural N0, whereas ypN + was associated with worse RFS. In multivariable analysis, ypN + independently predicted poor recurrence-free survival (HR 2.86, 95% CI 1.40-5.84). Among ypN0 patients, adjuvant immunotherapy was not associated with improved RFS or OS. CONCLUSIONS:Post-treatment nodal status is a key prognostic marker after neoadjuvant chemo-immunotherapy in resectable NSCLC. Patients with ypN0 had comparable outcomes regardless of clinical nodal stage, and selected ypN0 patients may not require adjuvant immunotherapy.

ABSTRACT The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a critical communication hub that translates extracellular signals into gene expression programs. Its aberrant activation serves as a central driver of tumorigenesis, metastasis, and immunosuppression in diverse malignancies. With research expanding from hematologic malignancies to solid tumors, the JAK/STAT pathway has gradually emerged as a promising therapeutic target for cancer treatment. This review systematically analyzes the multi‐dimensional dysregulation of the JAK/STAT pathway, encompassing somatic mutations, epigenetic modifications, and aberrant cytokine networks. We elucidate critical non‐canonical functions that underpin metabolic reprogramming and chromatin stability. Furthermore, we detail the pathway's pivotal role in bridging tumor cells with the microenvironment, focusing on myeloid‐derived suppressor cells (MDSC) recruitment and the reciprocal STAT3/PD‐L1 axis that fuels immune evasion and therapeutic resistance. Finally, we comprehensively evaluate the shifting therapeutic landscape, advocating for a transition from broad‐spectrum kinase inhibitors to high‐precision modalities such as allosteric modulators, proteolysis targeting chimeras (PROTACs), and novel combination strategies. By integrating the advance in the JAK/STAT pathway with cancer, this review underscores the potential of targeting this signaling axis for cancer therapy.

e12578 Background: Nipple discharge is a prevalent symptom affecting about 80% of women during reproductive years, yet only less than 5% of such cases are malignant. However, accurate non-invasive diagnosis in these women remains a longstanding clinical challenge. Here, we evaluated somatic copy number variations (CNVs) in nipple discharge DNA (ndDNA) as diagnostic biomarkers and explored their cellular origins. Methods: Breast cancer-specific CNV features were first derived from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA; 1,086 tumors and 942 controls). A diagnostic model constructed from these features was then tested in two in-house cohorts: nipple discharge (39 malignant, 18 benign) and plasma cell-free DNA (cfDNA; 149 malignant, 34 benign). To trace the cellular origin of nipple discharge CNVs, we performed single-cell RNA-sequencing on matched tumor tissues (n=5) and integrated the resulting inferCNV profiles with nipple discharge CNV profiles at single-cell level. Results: We identified 20 recurrent somatic CNVs (12 amplifications and 8 deletions). The diagnostic model demonstrated robust diagnostic performance in four external validation datasets. In the nipple discharge cohort, it achieved 74.4% sensitivity and 94.4% specificity for malignancy. In contrast, no significant CNV feature was detected in the plasma cfDNA cohort. Paired analysis revealed high concordance between nipple discharge CNVs and inferCNV. CNV release fidelity varied among epithelial subclusters. High-fidelity subsets displayed greater CNV burden, active estrogen signaling, and stronger immune interactions, and were associated with better prognosis. Conclusions: Our findings provide the first definitive evidence that nipple discharge is a tumor-proximal, highly specific non-blood liquid biopsy for breast cancer—surpassing plasma cfDNA by preserving tumor genomic signatures with minimal dilution and background noise. Beyond diagnostics, single-cell tracing deciphers luminal epithelial subcluster-selective ndDNA shedding, illuminating biomarker release mechanisms and advancing liquid biopsy paradigms across cancers.

BackgroundImmune escape remains a major barrier to durable benefit from immunotherapy in breast cancer, particularly in immune-cold tumors and those with an immune-excluded architecture. Emerging evidence from cancer neuroscience suggests that nerves are not passive bystanders of the tumor microenvironment, but active regulators of stromal remodeling, myeloid polarization, T-cell dysfunction, metastatic adaptation, and neuroendocrine stress biology.Main bodyWe synthesize current evidence supporting a multiscale model of neuro–immune crosstalk in breast cancer. We first examine sympathetic innervation as an upstream coordinator of immunosuppressive signaling through β-adrenergic pathways that reshape myeloid compartments, lymphangiogenesis, and effector lymphocyte fitness. We then discuss sensory-nerve-driven immune exclusion, focusing on CGRP–CAF–ECM circuits and Substance P-associated inflammatory relays that stabilize prometastatic states. Next, we review direct nerve–tumor interfaces, including neurotransmitter-dependent synapse-like signaling, pseudo-synaptic coupling, extracellular-vesicle/TNT-mediated metabolic communication, and mitochondrial transfer, and evaluate their potential roles in immune resistance and metastatic competence. We further integrate these local interactions into a systems framework by considering tumor–brain–sympathetic feedback loops and neuroendocrine outputs that reset host immune thresholds while emphasizing the context-dependent nature of neural regulation across tumor types and microenvironmental states. Finally, we summarize neurodevelopmental programs co-opted during metastasis, discuss emerging technologies for neural phenotyping and spatial analysis, and highlight clinically actionable vulnerabilities, including β-blockade, CGRP-axis modulation, RET/TRK-targeted therapy, and phenotype-guided combination strategies.ConclusionThis framework positions neural signaling as an upstream integrator of immune escape in breast cancer and suggests that neural biology may enable biologically informed stratification of immunotherapy-resistant tumors into distinct and targetable states.

Epidermal growth factor receptor (EGFR) mutations are major oncogenic drivers in non-small cell lung cancer (NSCLC), occurring in 30–50

Background:The infection of Pneumocystis jirovecii pneumonia (PJP) increases the rate of malignancy-related death. It is crucial to estimate the risk of PJP in this population. Peripheral blood neutrophil-to-lymphocyte ratio (NLR) has been proven to have significant value in predicting bacterial infection. However, the associations between peripheral blood NLR and PJP in patients with solid tumors have not been investigated. We aimed to identify whether baseline peripheral-blood NLR was correlated with PJP in patients with solid tumors. Methods:We retrospectively reviewed medical records of all consecutive patients with solid tumors and a proven diagnosis of PJP according to the European Organization for Research and Treatment of Cancer (EORTC) consensus definitions. Patients were randomly grouped into a discovery cohort and a validation cohort in a 2:1 ratio. Propensity score matching was performed in a 1:2 ratio between patients with PJP and those without PJP. Demographic and clinical data were collected, which included malignancy types, baseline NLR, chest imaging, coexisting pulmonary disease, and treatment regimens. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff value of NLR for analyzing risk of PJP. Multivariate logistic analysis was performed to identify the risk factors of PJP. Results:A total of 249 patients were included, of whom 83 had PJP infection and 166 did not. A total of 157 (63.1%) patients were aged 65 years or older, 73.5% of participants were male, and 37.3% were never-smokers. Patients with PJP had a higher NLR level than those without PJP (P<0.001). The optimal threshold of NLR to predict PJP was 6.22. Multivariate analysis revealed independent associations with higher NLR (odds ratio: 4.96; 95% confidence interval: 1.82-13.50; P=0.002) and PJP after adjustment for age, sex, and smoking status. The incidence of PJP in the high-NLR subgroup (NLR ≥6.22) was significantly higher than that in the low-NLR subgroup (NLR <6.22) in the discovery (65.3% vs. 19.8%; P<0.001) and validation cohorts (65.4% vs. 19.0%; P<0.001). Moreover, NLR was negatively correlated with absolute CD4 and CD8 cell count. Patients with high NLR had a lower mean absolute CD4 and CD8 cell count than those with low NLR. Conclusions:Among patients with solid tumors, a baseline feature of high NLR (≥6.22) was independently associated with an increased risk of PJP development. Furthermore, the NLR demonstrates potential utility in assessing immune status. Therefore, clinicians should consider initiating PJP prophylaxis earlier or performing earlier PJP screening in patients with solid tumors and elevated peripheral blood NLR.

Preserved Ratio Impaired Spirometry (PRISm) is a specific subtype of pre-chronic obstructive pulmonary disease (pre-COPD). People with PRISm are at risk of progression to chronic obstructive pulmonary disease (COPD). We developed a model to predict progression in subjects with PRISm. We screened 188 patients whose lung function transitioned from PRISm to COPD and 173 patients with PRISm who remained stable over two years. After excluding 78 patients due to incomplete clinical or laboratory data, a total of 283 patients were included in the final analysis. These patients were randomly divided into a training cohort (227 patients) and a validation cohort (56 patients) at a 8:2 ratio. LASSO regression and multivariate logistic regression were used to identify factors influencing progression. Among the 283 patients, 134 progressed to COPD. The model developed using six variables showed good performance, with areas under the receiver operating characteristic (ROC) curves of 0.87 in the training cohort and 0.79 in the validation cohort. The model demonstrated excellent calibration and was clinically meaningful, as shown by decision curve analysis (DCA) and clinical impact curve (CIC). We developed China’s first prediction model for the progression of lung function from PRISm to COPD in a real-world population. This model is conducive to early identification of high-risk groups of pulmonary function deterioration, so as to provide timely intervention and delay the occurrence and progression of the disease.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in non-small-cell lung cancer (NSCLC) with sensitizing mutations. However, patients with uncommon EGFR mutations show variable responses, and resistance often develops. The C797S mutation is a common resistance mechanism after third-generation EGFR-TKI osimertinib therapy, with no standard treatment established. A 37-year-old Chinese woman with advanced NSCLC harboring EGFR G719S/S768I mutations developed an acquired C797S mutation without T790M after second- and third-generation EGFR-TKI therapy. She was treated with a combination of gefitinib and bevacizumab, achieving a partial response, particularly in liver metastases. Her overall survival exceeded 60 months. Gefitinib combined with bevacizumab demonstrates efficacy in managing NSCLC with uncommon EGFR mutations and overcoming acquired C797S resistance. This combination therapy offers a promising treatment strategy for patients with limited options after resistance to second- and third-generation EGFR-TKIs.

Post-translational modifications (PTMs) play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality. PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short-chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation, and lactylation, differing from traditional acetylation in structure, physicochemical properties, function, and regulation. Aberrant short-chain acyl-PTMs are often associated with tumorigenesis. Research highlights that PTMs like succinylation and lactylation are essential in regulating tumor metabolism, drug resistance, and immune responses. This review elucidates the regulatory mechanisms of eight short-chain acyl-PTMs-butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, and lactylation-that are involved in tumor initiation and progression. Their roles in controlling tumor genomic stability, gene transcription, protein stability, enzyme activity, and nuclear localization are summarized, demonstrating their impact on related biological processes such as tumor metabolism, multi-drug resistance, and immune evasion. Additionally, the review provides an overview of current drug research targeting enzymes that regulate PTMs, offering critical insights to advance therapeutic strategies for cancer treatment.

Background:Indwelling pleural catheter (IPC) insertion is associated with fewer subsequent procedures and higher rates of spontaneous pleurodesis (SP) in patients with malignant pleural effusion (MPE). However, long-term pleural drains may cause psychological and physical distress. Additionally, only a portion of patients can benefit from IPC insertion and ultimately have them removed. The nomogram reflects the influence of different factors on outcome visually, enabling clinics to assess the optimal population. Thus, the objective of this study was to develop and validate a novel nomogram to predict successful SP in non-small cell lung cancer (NSCLC) patients with MPE treated with IPC. Methods:We reviewed data on the use of IPC insertion for MPE in patients with NSCLC and allocated them randomly to development (60%) and validation (40%) sets. A static and dynamic nomogram was developed based on multivariate logistic regression to evaluate SP occurrence in the development set. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and Nelson-Aalen cumulative risk curves were used to validate the predictive accuracy of the nomogram. Results:In total, 331 patients (development set: n=199; validation set: n=132) were selected for this study. Medical thoracoscopy, septated effusion, and effusion volume were the strongest predictors of SP. Other predictors included gender, systemic treatment, and serum neutrophil-to-lymphocyte ratio. The prediction nomogram was demonstrated good predictive ability in the development and validation sets (area under the curve: 0.745 and 0.720, respectively). The DCA indicated that the model had a certain clinical application value. Nelson-Aalen cumulative risk curves showed that the more favorable group received successful SP than did the less favorable group (P<0.001). Conclusions:We developed an accurate and practicable nomogram for successfully predicting SP. These results may benefit clinicians in optimizing treatment decisions, improving the probability of SP, and relieving the long-term discomfort caused by IPC.

Antibody-drug conjugate (ADC), a novel class of antineoplastic agents, combines tumor-specific targeting with potent cytotoxic activity. In recent years, ADC has achieved notable advances in the treatment of non-small cell lung cancer (NSCLC), particularly within therapeutic sequencing after failure of first-line therapy or the emergence of resistance. This paper will systematically review the efficacy and safety evidence of representative ADC in NSCLC, and further to discuss progress and challenges in ADC structural optimization, toxicity management, biomarker identification, and combination strategies, aiming to provide a comprehensive theoretical foundation and practical reference for clinical practice and future research.

ABSTRACT In this Phase II study, 13 patients with stage IIIB/IV non‐small cell lung cancer with acquired resistance to immune checkpoint inhibitors were treated with tislelizumab, sitravatinib, and docetaxel. The efficacy and safety were evaluated. The combination treatment achieved median progression‐free survival of 7.6 months, median overall survival of 17.2 months, an objective response rate of 58.3% (1 not evaluable), and a disease control rate of 100%. Grade ≥ 3 treatment‐related adverse events were primarily neutropenia and leukopenia. Exploratory analyses showed a trend toward increased T cell receptor (TCR) diversity following treatment. High pre‐treatment CD8+ T cell polyfunctional strength index (PSI) showed a trend toward association with early treatment response and deeper tumor shrinkage, while CD8+ PSI decreased post‐therapy in responders, although not significantly. Larger changes in CD4+ T cell PSI were associated with longer PFS. Although these data indicate clinical benefit and immunologic correlates, the limited sample size precludes definitive conclusions. Furthermore, the observed changes in TCR and PSI dynamics are preliminary, hypothesis‐generating, and may provide insights for optimizing therapeutic strategies. However, validation via large‐scale, randomized controlled clinical trials remains warranted. Trial registration: Chictr.org.cn, ChiCTR2200065547. Registered in 2022‐11‐08, https://www.chictr.org.cn/showproj.html?proj=183439.