bims-tuinly 2025-09-21 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–09–21
twenty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Chimeric antigen receptor T-cell (CAR T-cell) and tumor-infiltrating lymphocytes (TILs) therapies in gastrointestinal malignancies: review of literature for clinical applications.
Development of a murine tumor-infiltrating lymphocyte therapy model for cholangiocarcinoma.
Mathematical model of CISH knockout predicts increased efficacy in tumor-infiltrating lymphocyte activation with synergistic gene editing.
Expression of Programmed Cell Death Ligand 1 and Mismatch Repair Status in Ovarian Carcinomas.
Tumor-infiltrating lymphocytes and preoperative partial breast irradiation in early-stage breast cancer: insights from the prospective PAPBI cohort.
Dual checkpoint blockade of glioblastoma with Anti-PD-1 and Anti-LAG-3 promotes expansion of tumor-reactive T cell clones along a unique pathway of differentiation.
Current perspectives on Lifileucel tumor-infiltrating lymphocyte therapy: A paradigm shift in immunotherapy.
Tumor-specific but immunosuppressive CD39+CD8+ T cells exhibit double-faceted roles in clear cell renal cell carcinoma.
Claudin18.2 defines a prognostically distinct subgroup of intrahepatic cholangiocarcinoma via CD8+ T-cell exclusion.
Feasibility and Functional Reactivity of Expanded Tumor-infiltrating Lymphocytes from Non-clear-cell Renal Cell Carcinoma.
High-Fidelity AaCas12bMax Enables the Development of an Engineered T Cell Therapy with Enhanced Safety and Functional Fitness.
Therapeutic T cells with 3-in-1 strategy for the treatment of biliary tract cancer.
Case Report: Durable complete response to antigen-specific cytotoxic T lymphocyte therapy in advanced EGFR-TKI resistant lung adenocarcinoma: a case of adoptive cellular immunotherapy overcoming acquired targeted resistance.
Multi-adjuvant personalized neoantigen vaccines: Fine-tuning anti-cancer T cells.
Leveraging innate immune signals in CD8+ T cells to boost antitumor immunity.
USP14-mediated metabolic competition impairs CD8+ T cell immunosurveillance in hepatocellular carcinoma.
Dual targeting OX40 and IL-2 receptor enhances antitumor activity through tumor-infiltrating Treg depletion and CD8+ T-cell proliferation.
Urokinase-type plasminogen activator deficiency enhances CD8+ T cell infiltration and anti-PD-1 therapy efficacy in prostate cancer.
Novel Spectral High-Dimensional Flow Cytometry Assay for Combinatorial MHC Class I Tetramer Staining and Deep Antigen-Specific CD8+ T Cell Phenotyping.
The Potential of Magnetic Targeted Natural Killer Cell Therapy for Glioblastoma: An in Vivo Study of Natural Killer Cells Loaded With Low-Temperature Synthesized Folic Acid-Modified Superparamagnetic Iron Oxide Nanoparticles.
Comprehensive Analysis of Tumor Microenvironment and PD-L1 Expression Associations with Clinicopathological Features and Prognosis in Diffuse Large B-Cell Lymphoma.
Pathological complete response and survival outcomes in single hormone receptor-positive/HER2-negative breast cancer after neoadjuvant chemotherapy and its intrinsic biological features and immune landscape.
Prognostic value of combined tumor regression grade and TNM stage in muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.
Postoperative CA-125 as a Prognostic Marker for Overall Survival in Ovarian Cancer.
Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.
Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy.

Med Oncol. 2025 Sep 20. 42(11): 481

Chimeric antigen receptor T-cell (CAR T-cell) and tumor-infiltrating lymphocytes (TILs) therapies in gastrointestinal malignancies: review of literature for clinical applications.

Mohamed Saad Sayed, Ahmed Farid Gadelmawla, Osama Abouelenin, Elsayed S Moubarak, Nada S Jibril, Mahmoud Kandeel, Hebatullah Abdulazeem.

  Gastrointestinal malignancies (GI malignancies) have had a notoriously dismal prognosis throughout history. The primary therapeutic approaches to treat and manage GI malignancies are immunotherapy, radiotherapy, surgery, and chemotherapy, which may include monotherapy or a combination of these therapies to boost the effect. Nevertheless, the recurrence and metastasis rates remain elevated. In recent decades, immunotherapies have had a powerful impact when included in treatment regimens. In hematologic malignancy, chimeric antigen receptor T cells (CAR-T cell) have shown a promising anticancer impact as one of the immunotherapies. It gives a promising treatment option for solid tumors, including colorectal cancers. In recent clinical trials, the CAR-T cells showed a promising effect on pancreatic, colorectal, esophageal, hepatocellular, and gastric cancers. Tumor-infiltrating lymphocyte (TIL) therapy is another immunotherapy option with promising option for GI malignancies. Through the process of designing the TIL therapy, T cells are extracted and designed according to the nature of the GI malignancy. In this review, we addressed the clinical applications of both therapies while highlighting the challenges and possible strategies to overcome them. CAR T-cells and TIL therapies showed good responses with tolerable and acceptable side effects in treating GI malignancies such as pancreatic, colorectal, gastric, and hepatocellular cancers, while the immunosuppressive tumor microenvironment (TME) inhibiting the activity of immunotherapy and impeding its efficacy is a significant challenge.

Keywords:  CAR T-cells; Chimeric antigen receptor T cells; GI malignancies; Gastrointestinal malignancies; TIL therapy; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s12032-025-03040-5
J Immunol. 2025 Sep 16. pii: vkaf242. [Epub ahead of print]

Development of a murine tumor-infiltrating lymphocyte therapy model for cholangiocarcinoma.

Megen C Wittling, Frances J Bennett, Emilie A K Warren, Kailey M Oppat, Megan M Wyatt, Jacklyn N Hammons, Yuan Liu, Shishir K Maithel, Chrystal M Paulos, Gregory B Lesinski.

  Tumor-infiltrating lymphocyte (TIL) therapy is a promising approach, earning U.S. Food and Drug Administration approval in patients with anti-PD-1-resistant melanoma. Extending TIL therapy to patients with cholangiocarcinoma (CCA), an aggressive and largely immune-refractory cancer, is an emerging area of interest. However, cost and manufacturing complexity constrain clinical scalability of TIL therapy for CCA, underscoring the need for a murine model to optimize efficacy. Here, we established a novel orthotopic model of TIL therapy for CCA and tested a new ex vivo expansion strategy. We first characterized the immune landscape of orthotopic CCA and then compared 2 TIL expansion methods: (1) a conventional protocol using CD3 agonist stimulation (CD3 TILs) and (2) a tumor antigen-based protocol using irradiated autologous CCA cells to enrich for tumor-reactive TILs (Tumor Ag TILs). Tumor Ag TILs displayed superior tumor lysis in vitro compared to CD3 TILs. While both TIL products engrafted in vivo, Tumor Ag TILs showed enhanced persistence. Despite this, monotherapy with either TIL product alone had only a modest impact on tumor growth rate, and infused cells had upregulation of inhibitory checkpoint receptors, including PD-1. Further investigations demonstrated that the in vivo antitumor efficacy of both Tumor Ag TILs and CD3 TILs was enhanced when combined with PD-L1 inhibitor therapy. Altogether, our study establishes a preclinical platform for modeling CCA TIL therapy, identifies a rational combination strategy that potentiates TIL efficacy, and provides the field with a foundation to advance adoptive T-cell transfer development for CCA and related solid tumors.

Keywords:  Adoptive Cell Transfer (ACT); PD-L1 blockade; Tumor Infiltrating Lymphocytes (TILs); cholangiocarcinoma; orthotopic mouse model

DOI:  https://doi.org/10.1093/jimmun/vkaf242
bioRxiv. 2025 Sep 10. pii: 2025.09.05.674558. [Epub ahead of print]

Mathematical model of CISH knockout predicts increased efficacy in tumor-infiltrating lymphocyte activation with synergistic gene editing.

Nikolaos Memmos, Kamran Kaveh, Beau R Webber, Branden S Moriarity, David J Odde.

Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy, where the lymphocytes of a cancer patient's tumor are harvested, expanded in vitro using IL-2 stimulation, and then infused back into the patient[1], [2]. However, even with the use of TIL therapy, cancer cells can survive for various reasons, such as poor lymphocyte infiltration into tumors, chronic activation of the T cell receptor and the immunosuppressive tumor microenvironment[3]. Cytokine-inducible SH2-containing (CISH) protein is a negative regulator of T cell activation, and in a recent clinical trial was knocked out in TILs to improve TIL therapy efficacy[4]. In this study, we developed a mechanistic signaling pathway model to theoretically evaluate the efficacy of CISH knockout ( CISH KO) in T cell activation and examine potential alternative target genes that can theoretically be targeted using multiplex gene-editing or drugs to further improve T cell activation and function[5]. Our modeling results demonstrate that CISH knockout increases the transcription of activation biomarkers IL-2 and TNF-α, but also inhibitory biomarkers such PD1 and FasL. Using global sensitivity analysis, we also found that GSK3B , which is responsible for the deactivation of the NFAT, is also predicted to further increase T cell activation when knocked out. In addition, we predict that PDCD1, FAS and CTLA4 can be knocked-out in combination with CISH to further enhance T cell activation and prevent exhaustion and apoptosis.

DOI: https://doi.org/10.1101/2025.09.05.674558
J Midlife Health. 2025 Jul-Sep;16(3):16(3): 309-314

Expression of Programmed Cell Death Ligand 1 and Mismatch Repair Status in Ovarian Carcinomas.

Madhubala Hariprasad, Meenakshi Rao, Poonam Abhay Elhence, Jyotsna Naresh Bharti, Pratibha Singh, Garima Yadav, Aasma Nalwa, Hariprasad Ramalingam, Akhil Dhanesh Goel.

   Background: Ovarian carcinoma is the third most common gynecological malignancy among women in India, with a poor prognosis despite advancements in treatment modalities. Immunotherapy, particularly the use of programd cell death ligand 1 (PD-L1) checkpoint inhibitors, has emerged as a promising approach. This study investigates the relationship between PD-L1 expression, mismatch repair (MMR) status, and clinicopathological features in epithelial ovarian carcinoma (EOC).
Materials and Methods: A cohort of 50 EOC cases was analyzed for PD-L1 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) using immunohistochemistry (IHC). MMR status was also assessed through IHC. Statistical correlations between PD-L1 expression, MMR deficiency (dMMR), and clinicopathological parameters were evaluated.
Results: PD-L1 expression in tumor cells and TILs was observed in 20% and 14% of cases, respectively. PD-L1 expression in tumor cells was absent in most advanced-stage tumors (stages III and IV) and cases with extraovarian spread. dMMR was identified in 30% (n = 15) of cases, predominantly in higher-stage tumors with extraovarian spread and significant TIL presence (P = 0.007). However, PD-L1 expression in tumor cells and TILs was absent in 86.7% and 80% of dMMR cases, respectively. No significant association was found between dMMR status and PD-L1 expression in EOC.
Conclusion: PD-L1 expression in tumor cells is predominantly observed in early-stage EOC, suggesting its potential as a prognostic marker and therapeutic target. Although dMMR status correlates with advanced-stage disease and TIL presence, it does not significantly influence PD-L1 expression in EOC. These findings highlight the importance of routinely assessing PD-L1 and MMR status to guide immunotherapeutic strategies in ovarian carcinoma.

Keywords:  Epithelial ovarian carcinoma; immunotherapy; mismatch repair deficiency; ovarian carcinoma; programmed cell death ligand 1 expression; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.4103/jmh.jmh_102_25
Int J Radiat Oncol Biol Phys. 2025 Sep 11. pii: S0360-3016(25)06205-4. [Epub ahead of print]

Tumor-infiltrating lymphocytes and preoperative partial breast irradiation in early-stage breast cancer: insights from the prospective PAPBI cohort.

Jetske L B Gunster, Emma J Groen, Roberto Salgado, Corrie A M Marijnen, Astrid N Scholten.

   PURPOSE: Current understanding of the interaction between radiation therapy (RT) and tumor-infiltrating lymphocytes (TILs) is limited. We investigated the impact of preoperative accelerated partial breast irradiation (PAPBI) on TILs in early-stage breast cancer patients. Additionally, we evaluated whether baseline TILs were associated with pathologic response to RT.
METHODS: In the prospective PAPBI trial, early-stage breast cancer patients received preoperative RT (10 × 4 Gy or 5 × 6 Gy), followed by a wide local excision after six weeks. Matched control patients who underwent postoperative RT were retrospectively collected for validation. Stromal TILs (sTILs) were manually scored on hematoxylin- and eosin-stained slides from diagnostic biopsy and resection specimens, following established guidelines. Baseline differences in sTILs between patients with and without a pathologic complete response (pCR) were analyzed using the Mann-Whitney U test, and longitudinal changes in sTILs were evaluated with a linear mixed model.
RESULTS: A total of 72 PAPBI patients and 68 matched controls were included. In the PAPBI cohort, baseline sTILs were generally low, with a median of 2% (IQR 1 - 2%). Eight patients (11%) achieved a pCR, and these patients had significantly higher baseline sTILs compared to patients without a pCR (p = 0.021). Among the 64 PAPBI patients with evaluable pre- and post-irradiation samples, a minimal, non-significant increase in sTILs was observed following RT. Control patients had similarly low baseline sTILs (median 2%, IQR 1 - 2%), with no significant changes over time.
CONCLUSION: In this cohort of early-stage breast cancer patients receiving preoperative partial breast irradiation, longitudinal assessment showed minimal changes in sTILs after RT. In patients who achieved a pCR, we observed significantly higher baseline sTILs compared to those without a pCR.

Keywords:  breast cancer; partial breast irradiation; preoperative radiation therapy; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.ijrobp.2025.08.058
bioRxiv. 2025 Sep 11. pii: 2025.09.06.674490. [Epub ahead of print]

Dual checkpoint blockade of glioblastoma with Anti-PD-1 and Anti-LAG-3 promotes expansion of tumor-reactive T cell clones along a unique pathway of differentiation.

Mingshuang Wang, Yuntian Fu, Sadhana Bom, Yi Ning, Divij Matthews, Ming Zhang, Calixto-Hope Lucas, John Choi, Zhen Zeng, Tianbei Zhang, Hongkai Ji, Vasan Yegnasubramanian, Jon Weingart, Chetan Bettegowda, Kellie N Smith, Michael Lim, Drew Pardoll, Nancy R Zhang, Christina Jackson.

IDH-wildtype grade IV glioblastoma is the most aggressive adult primary brain tumor and remains refractory to anti-PD-1 monotherapy despite evidence of limited tumor-specific T cell induction. To determine the impact of immune checkpoint inhibitors (ICIs) on glioblastoma T cell transcriptional landscape and repertoire, we conducted paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR-seq) of tumor-infiltrating lymphocytes (TILs) from patients with untreated, newly diagnosed glioblastoma and from recurrent glioblastoma treated with dual checkpoint blockade targeting PD-1 and LAG-3. Using a validated transcriptional signature, we found that predicted tumor-reactive T cells (TRC) in untreated glioblastomas reside almost exclusively in a clonally expanded GZMK hi population with developmental plasticity, affording them the potential to differentiate into both tissue-resident and terminal effector T cells. Dual ICI therapy induced substantial clonal remodeling, characterized by the recruitment of new TRC from the periphery into the tumor microenvironment (TME) and differentiation into transitional effectors and ultimately terminal effectors along a gradient characterized by simultaneous acquisition of cytotoxic and exhaustion genes, regulated by specific transcriptional, metabolic, and epigenetic programs. Longitudinal clonal tracking in peripheral blood confirmed that with ICI treatment, most TRC expand transiently in circulation prior to tumor infiltration, with peripherally derived clones becoming the major contributor to the GZMK hi TRC that further expand in the tumor. Our study provides the first comprehensive map of T cell clonal dynamics and differentiation in glioblastoma following dual ICIs and highlights a potential mechanism of immune activation and peripheral recruitment of TRC in glioblastoma not previously described. Our results suggest that therapeutic strategies to sustain these GZMK hi early effector and transitional effector T cells may further enhance ICI therapeutic efficacy in glioblastoma.

DOI: https://doi.org/10.1101/2025.09.06.674490
Curr Probl Cancer. 2025 Sep 12. pii: S0147-0272(25)00079-0. [Epub ahead of print]59 101252

Current perspectives on Lifileucel tumor-infiltrating lymphocyte therapy: A paradigm shift in immunotherapy.

Simran Deep Kaur, Md Abubakar, Neena Bedi, Eswara Rao Puppala, Deepak N Kapoor, Nitesh Kumar, Nafees Ahemad, Sirajudheen Anwar.

  Lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy, provides renewed hope for individuals with advanced, treatment-resistant malignancies. This is a groundbreaking advancement in cancer immunotherapy. Revolutionizing the way the immune system fights cancer, this state-of-the-art cellular therapy takes advantage of TILs' innate capacity to target tumors. Lifileucel is an innovative medicine that is garnering attention in oncology. It has shown remarkable efficacy in clinical trials, assisting individuals unresponsive to other therapy in sustaining their responses and enhancing their survival rates. This paper provides a comprehensive overview of contemporary perspectives on Lifileucel, including its mechanism of action, clinical results, challenges and potential applicability to a broader spectrum of solid tumors. The Lifileucel concept has initiated a new epoch in personalized cancer therapy. This review offers a forward-looking perspective on the potential advancements and opportunities for establishing Lifileucel and TIL-based therapies as a cornerstone in cancer therapy.

Keywords:  Eastern cooperative oncology group (ECOG); Immune checkpoint inhibitors (ICIs); Interleukin-2 (IL-2); Lifileucel (AMTAGVI); Overall response rate (ORR); Tumor-Infiltrating Lymphocyte (TIL)

DOI:  https://doi.org/10.1016/j.currproblcancer.2025.101252
Cell Rep Med. 2025 Sep 16. pii: S2666-3791(25)00433-1. [Epub ahead of print] 102360

Tumor-specific but immunosuppressive CD39+CD8+ T cells exhibit double-faceted roles in clear cell renal cell carcinoma.

Yong Joon Lee, Seung Hyuck Jeon, Jin Hee Yeo, Sun-Ju Byeon, Jae Hyung Jung, Heejin Nam, Minwoo Jeon, Eui-Soon Kim, Jeon Yeob Jang, Chul-Ho Kim, Kee Yang Chung, Jung Yun Lee, Shin Hwang, Jee Ye Kim, Seung-Il Kim, Jae-Ho Cheong, Chang Gon Kim, Sang Joon Shin, Su-Hyung Park, Minsun Jung, Minyong Kang, Seong Il Seo, Eui-Cheol Shin.

  CD39+CD8+ T cells are known as tumor-antigen-specific cells among CD8+ tumor-infiltrating lymphocytes (TILs). However, CD39+CD8+ T cells also reportedly exhibit immunosuppressive activity in hypoxic tumor models. Here, we investigate CD39+CD8+ TILs in clear cell renal cell carcinoma (ccRCC), a Von Hippel-Lindau (VHL) mutation-associated hypoxic tumor. Single-cell analyses confirm that CD39+CD8+ cells are a terminally exhausted subset of tumor-specific CD8+ TILs. CD39+CD8+ T cell development is directly induced by cAMP and T cell receptor (TCR) signaling. Analysis of a renal cell carcinoma (RCC) cohort reveals that the proportion of CD39+CD8+ TILs is associated with a high tumor mutational burden and hypoxic features. Ex vivo functional assays reveal that CD39+CD8+ TILs exert immunosuppressive activity via ectonucleotidase activity- and adenosine-dependent mechanisms. CD39+CD8+ TIL enrichment predicts poor prognosis in patients with ccRCC yet also predicts favorable treatment responses to anti-programmed cell death protein 1 (PD-1) therapy. This paradoxical prognostic significance in ccRCC is explained by the dual properties of CD39+CD8+ TILs: tumor antigen specificity and immunosuppressive activity.

Keywords:  CD39(+)CD8(+) T cells; adenosine pathway; anti-PD-1 therapy; clear cell renal cell carcinoma; hypoxia; immunosuppressive activity; paradoxical prognosis; tumor antigen specificity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2025.102360
Front Oncol. 2025 ;15 1636367

Claudin18.2 defines a prognostically distinct subgroup of intrahepatic cholangiocarcinoma via CD8+ T-cell exclusion.

Chengui Yu, Yuren Pan, Fuli Li, Zhenyun Guo, Da Xu, Ying Zhu, Baobing Yin.

   Background and purpose: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited therapeutic options. Claudin18.2 (CLDN18.2), a tight junction protein aberrantly expressed in gastrointestinal cancers, has not been systematically evaluated in ICC. This study investigates CLDN18.2's expression, clinical relevance, and interplay with the tumor immune microenvironment (TIME) in ICC.
Method: CLDN18.2 expression was analyzed in 83 ICC and 47 matched non-tumor tissues on tissue microarray sections using immunohistochemistry (IHC). Bioinformatics validation utilized ArrayExpress (E-MTAB-6389) and GEO (GSE119336, GSE107943, GSE89749, GSE32225) datasets. Clinicopathological correlations, survival analysis, and CD8+ tumor-infiltrating lymphocytes (TILs) quantification were performed.
Results: CLDN18.2 was exclusively expressed in 24.1% (20/83) of ICC tissues, absent in non-tumor tissues. Positive CLDN18.2 expression correlated with elevated serum CA19-9 (P = 0.026), smaller tumor size (P = 0.03), unifocality (P = 0.03), and higher recurrence (P = 0.018). Multivariable analysis identified CLDN18.2 as an independent prognostic factor for reduced overall survival (OS: HR = 2.555, 95% CI = 1.250-5.223, P = 0.01) and disease-free survival (DFS: HR = 2.229, 95% CI = 1.125-4.415, P = 0.022). Single-sample gene set enrichment analysis (ssGSEA) analysis revealed an inverse correlation between CLDN18 expression and CD8+ T cells (P = 0.012), while IHC showed a trend toward negative correlation between CLDN18.2 expression and CD8+ TILs density (P = 0.12). Combined stratification showed optimal OS in CLDN18.2-/CD8high patients versus worst outcomes in CLDN18.2+/CD8low subgroup (P = 0.006).
Conclusions: CLDN18.2 is a tumor-specific prognostic biomarker in ICC, marking aggressive subsets with early recurrence. Combined CLDN18.2/CD8+ TILs stratification enhances prognostic precision and suggests synergistic potential for CLDN18.2 targeted therapies with immunomodulation. These findings warrant clinical validation to guide personalized treatment strategies.

Keywords:  CD8+ T-cell; CLDN18.2; clinicopathological features; intrahepatic cholangiocarcinoma; prognosis

DOI:  https://doi.org/10.3389/fonc.2025.1636367
Eur Urol. 2025 Sep 16. pii: S0302-2838(25)00491-9. [Epub ahead of print]

Feasibility and Functional Reactivity of Expanded Tumor-infiltrating Lymphocytes from Non-clear-cell Renal Cell Carcinoma.

Marine Potez, Seyed Behzad Jazayeri, Christopher Guske, Justin Miller, Johannes Ali, Michael Carter, Fatema Khambati, Jasreman Dhillon, Wade Sexton, Logan Zemp, Brandon Manley, Gabriel Roman Souza, Philippe E Spiess, Matthew Beatty, Shari Pilon-Thomas, Jad Chahoud.

DOI: https://doi.org/10.1016/j.eururo.2025.09.002
Mol Ther. 2025 Sep 12. pii: S1525-0016(25)00737-3. [Epub ahead of print]

High-Fidelity AaCas12bMax Enables the Development of an Engineered T Cell Therapy with Enhanced Safety and Functional Fitness.

Jingwei Sun, Ke Liu, Yao Sheng, Hongwei Zhang, Jingman Wang, Yueqiang Wang, Rui Tian, Xi Zhu, Shin-Shay Tian, Pin Wang, Xiaoping Zhao, Yarong Liu.

CRISPR-Cas systems have transformed genome editing, yet the commonly used Streptococcus pyogenes Cas9 (SpCas9) is limited by off-target effects and chromosomal instability. Here, we characterize AaCas12bMAX, an engineered Alicyclobacillus acidiphilus Cas12b variant, as a high-precision editing platform optimized for tumor infiltrating lymphocyte (TIL) therapy. Using an FDA-compliant safety assessment framework, we systemically compared AaCas12bMAX- and SpCas9-edited TIL products in terms of on-target efficiency, genome-wide off-target activity, and structural variants (SVs) formation. AaCas12bMAX achieved >80% on-target editing efficiency with undetectable off-target events and a 3.3-fold reduction in SVs relative to SpCas9. Mechanistic studies revealed different DNA repair kinetics in AaCas12bMAX-edited cells, reducing sustained DNA damage responses and chromosomal instability. Structural modeling suggested a more stable enzyme-sgRNA-DNA ternary complex, enabling stringent PAM specificity and minimal mismatch tolerance. Functionally, AaCas12bMAX-edited TILs exhibited superior therapeutic potential, including enhanced cellular fitness, a twofold increase in expansion capacity, and enrichment of stem-like tumor-reactive CD39-CD69-CD8+ subsets. Together, these results establish AaCas12bMAX as a robust, clinically translatable platform that improves the safety and functional limitations of SpCas9, enabling the development of next-generation T cell therapies.

DOI: https://doi.org/10.1016/j.ymthe.2025.09.009
Cell Rep Med. 2025 Sep 18. pii: S2666-3791(25)00422-7. [Epub ahead of print] 102349

Therapeutic T cells with 3-in-1 strategy for the treatment of biliary tract cancer.

Xueshuai Wan, Jie Zhao, Xiaobo Yang, Xianing Mou, Bing Liu, Bin Gao, Weiyue Gu, Haitao Zhao.

  T cell therapy for tumors faces barriers like heterogeneous antigen expression, an unfriendly tumor microenvironment, and limited T cell expansion. We adopt a 3-in-1 strategy to produce super circulating TIL-like (tumor-infiltrating lymphocyte-like) cells (ScTILs): modifying PD-1-positive peripheral blood T cells with an enhance receptor (ER), a PD-1 and CD28 fusion protein to reverse inhibitory signal, and an anti-CD19 chimeric antigen receptor (CAR) for expansion (CFE). ScTILs kill tumor cells effectively in vitro and in vivo. Clinically, ten advanced biliary tract cancer (BTC) patients receive ScTILs treatment; post hoc analysis shows that ScTILs monotherapy yields a median overall survival (OS) of 18.3 months in appropriate dose or normal B cell groups (5/10), outperforming first-line BTC treatment (OS ∼12 months). It skips chemo-pre-treatment and interleukin-2 (IL-2), with better safety, no reliance on surgical materials, and a shorter production cycle. Overall, ScTILs are a promising therapy for future BTC treatment. This study is registered with ChiCTR (ChiCTR2000029738).

Keywords:  3-in-1 T cells; CAR for expansion of T cells; CAR-T for solid tumors; PD-1 positive T cell selection; T cell expansion in vivo; TILs like cells; biliary tract cancer therapy; checkpoint inhibition; enhance receptor; super circular tumor-infiltrating lymphocytes (ScTILs)

DOI:  https://doi.org/10.1016/j.xcrm.2025.102349
Front Immunol. 2025 ;16 1637165

Case Report: Durable complete response to antigen-specific cytotoxic T lymphocyte therapy in advanced EGFR-TKI resistant lung adenocarcinoma: a case of adoptive cellular immunotherapy overcoming acquired targeted resistance.

Chenghao Fu, Chengyu Bian, Weiyou Zhu, Haonan Du, Linrui Han, Jian Zhu, Jun Wang, Lei Cao.

  Adoptive cell therapy (ACT), an important component of tumor immunotherapy, achieves precise anti-cancer effects by reinfusing in vitro-processed immune cells, providing a new option for advanced tumor patients with resistance to chemotherapy or targeted therapy. Among them, antigen-specific cytotoxic T lymphocyte (ACTL) therapy innovatively integrates the natural expansion advantage of tumor-infiltrating lymphocytes (TILs) and the precise antigen-presenting mechanism of recombinant adeno-associated virus-transfected dendritic cells (rAAV-DCs), becoming a research focus. This case report describes a patient with IVa stage advanced lung adenocarcinoma with multiple intrapulmonary metastases carrying an epidermal growth factor receptor (EGFR) exon 19 deletion mutation. After receiving treatment with the third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) drug osimertinib, the patient developed acquired resistance with unknown mechanisms and was in an immune-suppressed state. Subsequently, the patient received ACTL therapy and ultimately achieved a clinical complete response (cCR) and maintained it for six years of follow-up. This case is the first to report that ACTL therapy has achieved "clinical cure" in a patient with acquired EGFR-TKI resistance, indirectly suggesting the underlying mechanism of this therapy in reshaping the tumor immune microenvironment (TME). It illustrates that ACTL, as a novel cellular immunotherapy with both target precision and immune balance, has demonstrated potential in overcoming targeted resistance in advanced lung cancer and inducing deep remission.

Keywords:  ACTL; EGFR-TKI; advanced NSCLC; cellular immunotherapy; resistance

DOI:  https://doi.org/10.3389/fimmu.2025.1637165
Cell. 2025 Sep 18. pii: S0092-8674(25)00980-8. [Epub ahead of print]188(19): 5121-5123

Multi-adjuvant personalized neoantigen vaccines: Fine-tuning anti-cancer T cells.

Hejia Henry Wang, Neeha Zaidi.

Personalized cancer vaccines aim to broaden the anti-tumor T cell repertoire by targeting neoantigens unique to each patient's tumor, but immunogenicity has been inconsistent. In this issue of Cell, Blass, Keskin, Tu et al. evaluate NeoVaxMI, a multi-adjuvant personalized synthetic long-peptide vaccine administered with nivolumab in patients with melanoma. NeoVaxMI elicited stronger CD4+ and CD8+ responses than earlier iterations, and vaccine-induced T cells trafficked to regressing metastatic lesions.

DOI: https://doi.org/10.1016/j.cell.2025.08.025
Front Immunol. 2025 ;16 1617773

Leveraging innate immune signals in CD8+ T cells to boost antitumor immunity.

Gabriella K Albert, Phoebe Cao, Eduardo Davila.

  Pattern recognition receptors (PRRs), traditionally characterized in innate immune cells, are emerging as critical modulators of T cell function. Toll-like receptors (TLRs), STING, RIG-I-like receptors (RLRs), and natural killer receptors (NKRs) are expressed by CD8+ T cells, where they influence various cellular responses. Primarily serving as noncanonical costimulatory signals, TLRs can modulate T cell activation, differentiation, metabolic fitness, and memory formation. RLRs and STING can promote T cell expansion and cytokine production. Both activating and inhibitory NKRs can also alter T cell cytotoxicity and differentiation. As demonstrated in recent advancements, the capacity of these signaling cascades to enhance T cell responses offers promising therapeutic opportunities in cancer. Clinical strategies are being developed to selectively harness each of these pathways, such as TLR and STING agonists to bolster antitumor responses, and NKR-based approaches to amplify cytotoxic function. Additionally, adoptive T cell therapies, such as chimeric antigen receptor (CAR)-T cells, are incorporating these innate signaling components to overcome tumor-mediated immunosuppression, enhance functional longevity, and improve therapeutic efficacy. This review discusses the progress made to characterize the role of T cell intrinsic PRR activity in shaping T cell functions and highlights recent advancements in that leverage innate receptor signaling to enhance the efficacy of cancer immunotherapies.

Keywords:  T cell immunotherapy; antitumor immunity; innate receptor signaling; innate-like stimulation; pattern recognition receptors

DOI:  https://doi.org/10.3389/fimmu.2025.1617773
Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2510576122

USP14-mediated metabolic competition impairs CD8+ T cell immunosurveillance in hepatocellular carcinoma.

Yichuan Yuan, Yi Niu, Zhenkun Huang, Yunxing Shi, Zhu Lin, Dinglan Zuo, Chengrui Zhong, Kai Li, Xin-Yuan Guan, Yunfei Yuan, Binkui Li.

  Hepatocellular carcinoma (HCC) frequently develops resistance to CD8+ T cell-based immunotherapy, yet the mechanisms driving this immune evasion remain poorly understood. To identify tumor-intrinsic regulators of immunotherapy resistance and explore therapeutic strategies to restore T cell-mediated tumor control, we employed three functional genomics approaches using in vitro and in vivo CRISPR screening. Cancer USP14 was identified as the critical immune evasion driver. USP14-high HCC patients exhibited poorer anti-PD1 antibody therapy responses and reduced CD8+ T cell infiltration. Inhibition of USP14 suppressed HCC cell growth in coculture with activated CD8+ T cells and restored cocultured CD8+ T cell cytotoxicity. In vivo USP14 targeting synergized with anti-PD1 antibody therapy. Mechanistically, USP14 deubiquitinated and stabilized GLUT1 through the removal of Lys-48-linked ubiquitin chains at Lys-245, which enabled HCC cells to outcompete CD8+ T cells for glucose, generating a glucose-deprived tumor microenvironment that suppressed CD8+ T cell function. Our findings show USP14 in cancer has a proimmunoevasive role in CD8+ T cell-based tumor immunity through GLUT1-mediated glucose competition. These findings position USP14 inhibitors as promising adjuvants to enhance immunotherapy efficacy in HCC, providing actionable insights for overcoming resistance.

Keywords:  GLUT1; USP14; glucose competition; hepatocellular carcinoma

DOI:  https://doi.org/10.1073/pnas.2510576122
J Immunother Cancer. 2025 Sep 15. pii: e011638. [Epub ahead of print]13(9):

Dual targeting OX40 and IL-2 receptor enhances antitumor activity through tumor-infiltrating Treg depletion and CD8+ T-cell proliferation.

Shuaishuai Cao, Zhichen Sun, Wenbo Hu, Diyuan Xue, Zuming Yang, Pengfei Duan, Hua Peng, Yang-Xin Fu, Yong Liang.

   BACKGROUND: The strong regulatory T cell (Treg) inhibitory activity and dysfunctional cytotoxic T lymphocytes (CTLs) represent major barriers to effective antitumor immunity, particularly in late-stage cancer. Multiple anti-OX40 (aOX40) agonistic antibodies have been developed but exhibit limited antitumor efficacy. Interleukin-2 (IL-2) effectivity expands CTLs but has severe side effects.
METHODS: We construct an aOX40-mIL2-Fc bispecific antibody through Fab physical blocking and attenuated IL-2 with Rβ reducing N88D mutation. We also produced aOX40-Fc and IL-2/aOX40-Fc as a comparison using the 293F expression system. Single-cell and flow cytometry were used to analyze the change of T-cell subsets in the tumor microenvironment (TME). Mouse tumor models were used to assess the antitumor efficacy of aOX40-mIL2-Fc by tumor growth and survival, and toxicity by body weight loss, inflammatory cytokine production, and natural killer (NK) cell proliferation in the blood. The tumor-bearing mice were randomly assigned, and the average size was similar among various groups.
RESULTS: aOX40-mIL2-Fc bispecific antibody-cytokine exhibited a synergistic therapeutic effect with limited toxicity, outperforming IL-2-Fc or aOX40 alone treatment, and conferring resistance to tumor rechallenge. On cellular mechanisms, aOX40-mIL2-Fc treatment showed great Treg depletion and increased both stem-like and effector functional terminal CD8+ T cells in the TME, while avoiding NK cells expansion in the periphery. Furthermore, this bispecific antibody remarkably improved the anti-programmed death-ligand 1 (PD-L1) therapeutic effect.
CONCLUSIONS: Our study unveils a novel approach to IL-2 design that addresses several critical shortcomings of existing strategies and elucidates the cellular mechanisms underlying aOX40-mIL2-Fc therapy. Meanwhile, combining aOX40-mIL2-Fc with PD-L1 blockade represents a strategic approach to enhance tumor control and overcome resistance to immune checkpoint blockade therapies synergistically.

Keywords:  Cytokine; Immunotherapy; Tumor infiltrating lymphocyte - TIL; co-stimulatory molecules

DOI:  https://doi.org/10.1136/jitc-2025-011638
Front Immunol. 2025 ;16 1625226

Urokinase-type plasminogen activator deficiency enhances CD8+ T cell infiltration and anti-PD-1 therapy efficacy in prostate cancer.

Xiaoyi Li, Xiao Zhang, Xing Fu, Hong Wu, Xinyu Ye, Xin Huang, Yuhao Cui, Chao-Nan Qian, Yi Lu, Jian Zhang.

   Introduction: Urokinase-type plasminogen activator (uPA) is upregulated in prostate cancer, but its comprehensive impact on the immune microenvironment and the underlying mechanisms remains to be fully elucidated.
Methods: uPA expression was analyzed in clinical prostate cancer specimens and correlated with CD8⁺ T cell infiltration. Tumor growth was assessed in the uPA-deficient (uPA-/-)and the uPA inhibitor UK122-treated mouse model. Immune infiltration was evaluated by CyTOF and flow cytometry. Anti-CD19 chimeric antigen receptor (CAR)-engineered WT or uPA-/- CD8⁺ T cells were tested for cytotoxicity against RM1-CD19 cells. The combination of UK122 and anti-PD-1 therapy was assessed.
Results: Elevated uPA in prostate cancer specimens inversely correlated with CD8⁺ T cell infiltration. Both genetic uPA ablation and UK122 significantly attenuated tumor growth by enhancing antitumor immunity. uPA deficiency markedly increased CD8⁺ T cell infiltration. uPA-/- CD8⁺ T cells exhibited enhanced cytotoxicity compared to WT CD8⁺ T cells. Tumor-infiltrating uPA-/- CD8⁺ T cells showed higher PD-1 expression. UK122 synergized with anti-PD-1 therapy to promote tumor regression.
Discussion: uPA is a significant immunosuppressive regulator in prostate cancer. Its inhibition enhances CD8⁺ T cell function and synergizes with immune checkpoint blockade, supporting uPA targeting as a novel strategy to improve prostate cancer immunotherapy efficacy.

Keywords:  CD8+ T cells; combination therapy; prostate cancer; tumor immune microenvironment; urokinase-type plasminogen activator

DOI:  https://doi.org/10.3389/fimmu.2025.1625226
Cytometry A. 2025 Sep 18.

Novel Spectral High-Dimensional Flow Cytometry Assay for Combinatorial MHC Class I Tetramer Staining and Deep Antigen-Specific CD8+ T Cell Phenotyping.

William Pratcher, Chikara Takahashi, Maria Lorenzo, Alberto Robert, Jiun Chiun Chang, Leesun Kim, Daniel Haensel, Martine Darwish, Mahesh Yadav, William E O'Gorman, Thomas Liechti.

  Cytotoxic CD8+ T cells eliminate virus-infected or cancer cells, thus playing a pivotal role in anti-viral and anti-cancer immunity. Tetramer reagents, which consist of fluorochrome-labeled streptavidin coupled with peptide-loaded MHC I molecules, enable the detection of antigen-specific CD8+ T cells using flow cytometry. The development of tetramer reagents has been instrumental for our understanding of antigen-specific CD8+ T cells and their roles in immune responses. More recently, combinatorial tetramer staining protocols have enabled the simultaneous detection and monitoring of multiple specificities and concomitant pathogen-dependent CD8+ T cell dynamics. However, these methods are either based on mass cytometry, preventing the isolation of antigen-specific CD8+ T cells for downstream investigation, or have provided a less comprehensive picture of the phenotypic characteristics of antigen-specific CD8+ T cells when based on flow cytometry. Here we describe the development of a combinatorial tetramer staining protocol in combination with high-dimensional CD8+ T cell immunophenotyping in the context of virus-specific CD8+ T cells leveraging spectral flow cytometry. Our assay enables the simultaneous measurement of 15 different CD8+ T cell specificities and includes an additional 18 markers to define the phenotypic and functional characteristics of antigen-specific CD8+ T cells. We describe our assay optimization strategies, with the goal of improving marker and tetramer resolution while eliminating sources of background noise. Finally, we apply this method to reveal the phenotypic heterogeneity of virus-specific CD8+ T cells against common viral pathogens in healthy individuals.

Keywords:  Cytomegalovirus; Epstein–Barr virus; MART1; antigen‐specific T cells; combinatorial tetramer staining; high‐dimensional flow cytometry; influenza; unsupervised data analysis; virology

DOI:  https://doi.org/10.1002/cyto.a.24959
Neurosurgery. 2025 Sep 19.

The Potential of Magnetic Targeted Natural Killer Cell Therapy for Glioblastoma: An in Vivo Study of Natural Killer Cells Loaded With Low-Temperature Synthesized Folic Acid-Modified Superparamagnetic Iron Oxide Nanoparticles.

Pao-Chun Lin, Ya-Jyun Liang, Wei-Ting Kuo, Feng-Huei Lin, Fon-Yih Tsuang.

   BACKGROUND AND OBJECTIVES: Glioblastoma (GBM) is a highly malignant brain tumor with limited treatment options. While natural killer (NK) cell-based immunotherapy shows promise in cancer treatment, effective tumor targeting remains a challenge. This study investigates the use of folic acid-modified superparamagnetic iron oxide nanoparticles (SPIONs-PEG-FA) to magnetize NK cells, enabling them to accumulate at the tumor site under an external magnetic field while retaining their cytotoxic activity against GBM cells.
METHODS: SPIONs-PEG-FA were synthesized using PEGylation and coprecipitation to ensure efficient NK cell uptake. Their successful synthesis was confirmed through material characterization, including X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, and dynamic light scattering. In vitro studies evaluated their safety, cellular uptake, and cytolytic activity, whereas in vivo experiments assessed tumor targeting and therapeutic efficacy in GBM-bearing mice.
RESULTS: SPIONs-PEG-FA-loaded NK cells were successfully developed for targeted GBM therapy. In vitro studies confirmed their safety and effectiveness against GBM tumor cells, whereas transmission electron microscopy analysis verified the cellular uptake of SPIONs-PEG-FA by NK cells. In vivo experiments in GBM-bearing mice demonstrated improved tumor targeting, enhanced cytolytic efficiency, and overall safety of SPIONs-PEG-FA-loaded NK cells.
CONCLUSION: SPIONs-PEG-FA-loaded NK cells represent a promising approach for targeted GBM therapy. Their successful synthesis and characterization, coupled with in vitro and in vivo validation, highlight their potential for improved therapeutic outcomes. This magnetic field-guided NK cell therapy offers a promising strategy for overcoming challenges in GBM treatment.

Keywords:  Glioblastoma; Immunotherapy; NK cell; Superparamagnetic iron oxide

DOI:  https://doi.org/10.1227/neu.0000000000003731
Blood Lymphat Cancer. 2025 ;15 167-179

Comprehensive Analysis of Tumor Microenvironment and PD-L1 Expression Associations with Clinicopathological Features and Prognosis in Diffuse Large B-Cell Lymphoma.

Yun-Li Xie, Long-Feng Ke, Wen-Wen Zhang, Fu Kang, Shu-Yi Lu, Chen-Yu Wu, Huan-Huan Zhu, Jian-Chao Wang, Gang Chen, Yan-Ping Chen.

   Introduction: The tumor microenvironment (TME) influences diffuse large B-cell lymphoma (DLBCL) progression, but the prognostic roles of tumor-infiltrating T-lymphocytes (TIL-T), tumor-associated macrophages (TAMs), and PD-L1 remain undefined. This study investigates the clinicopathological associations and prognostic impacts of TIL-T, TAMs, and PD-L1 expression in DLBCL.
Methods: This retrospective study evaluated 89 primary DLBCL cases, integrating clinicopathological data with automated immunohistochemical quantification of CD3, CD8, FOXP3, CD163, and PD-L1 expression in tumor hotspots and microenvironmental compartments. Prognostic associations of TIL-T, TAMs, and PD-L1 expression with PFS and OS were analyzed via Kaplan-Meier methods and Cox regression.
Results: High CD3+ infiltration correlated with lower Ki-67 expression, while elevated FOXP3+ levels linked to improved Eastern Cooperative Oncology Group Performance Status (ECOG). CD163+ TAMs varied by NCCN-IPI risk, ECOG, and cell of origin. Neoplastic PD-L1 (nPD-L1) positivity associated with higher NCCN-IPI scores, CD3+ T-cell infiltration, and CD163+ TAM enrichment. Microenvironmental PD-L1 (mPD-L1) correlated with age, ECOG, B symptoms, and infiltration of all T-cell subsets and TAMs. Survival analysis revealed prolonged overall survival (OS) with high CD3+, CD8+, FOXP3+ TIL-T, CD163+ TAMs, or mPD-L1 positivity, while progression-free survival (PFS) improved with CD3+ infiltration and mPD-L1. Univariate analysis identified B symptoms, extranodal involvement, and low TIL-T levels as OS risks, whereas ECOG 0 and mPD-L1+ were protective. Multivariate modeling confirmed B symptoms, extranodal disease, and CD3+ TIL-T as independent OS predictors; CD3+ TIL-T and B symptoms independently impacted PFS.
Discussion: The TME plays a crucial role in the biological behavior of DLBCL, particularly because TIL-T and TAMs are significantly associated with patient survival outcomes. These cell types may serve as critical biomarkers and provide novel immunotherapy targets in DLBCL.

Keywords:  diffuse large B-cell lymphoma; programmed death-ligand 1; tumor microenvironment; tumor-associated macrophages; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.2147/BLCTT.S545717
Breast Cancer Res Treat. 2025 Sep 17.

Pathological complete response and survival outcomes in single hormone receptor-positive/HER2-negative breast cancer after neoadjuvant chemotherapy and its intrinsic biological features and immune landscape.

Lei Ji, Xi Chen, Hongwei Lyu, Ge Song, Min Xiao, Qing Li, Jiayu Wang, Ying Fan, Yang Luo, Qiao Li, Shanshan Chen, Fei Ma, Binghe Xu, Pin Zhang.

   BACKGROUND: Previous studies often combined double hormone receptor-positive (dHR +) and single HR-positive (sHR +) tumors, thus not accounting for the distinct characteristics of sHR + , particularly in the neoadjuvant setting. Moreover, adding immunotherapy to cytotoxic chemotherapy has shown encouraging efficacy in certain HR-positive early breast cancers. This study sought to assess pathological complete response (pCR) and survival outcomes in sHR + /HER2- breast cancer after neoadjuvant chemotherapy, while also investigating its specific biological traits and immune profile.
METHODS: Clinical data were sourced from the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS, n = 1049), and the Surveillance, Epidemiology, and End Results (SEER, n = 21,092) database to examine neoadjuvant chemosensitivity and survival outcomes. Additionally, clinicopathological and subtype data from CHCAMS, SEER, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1052), and Fudan University Shanghai Cancer Center (FUSCC, n = 570) were analyzed to identify biological features that correlate with pCR rates and prognosis in sHR + /HER2- breast cancer. Further genomic and transcriptomic data from METABRIC, The Cancer Genome Atlas (TCGA, n = 741), and MSK-IMPCAT (n = 1535) were reviewed to uncover their potential links with endocrine and immunotherapy responses.
RESULTS: In comparison to dHR + (ER + and PR +)/HER2- breast cancer, sHR + (ER + /PR- or ER-/PR +)/HER2- breast cancer displayed a higher pCR rate (20.2% vs. 3.2%, P < 0.001), but considerably worse survival (hazard ratio, 2.97; 95% confidence interval, 1.62-5.43, P < 0.001) within the CHCAMS neoadjuvant cohort. Clinically, sHR + /HER2- tumors were associated with higher histological grades and proliferation rates compared to dHR + /HER2- tumors, along with a greater rate of HR-low positivity (50.9% vs. 3.0%, P < 0.001) in primary tumors and a tendency to transition to triple-negative tumors in residual disease (42.7% vs. 1.8%, P < 0.001). Furthermore, sHR + /HER2- breast cancers demonstrated lower endocrine sensitivity scores, with about 20% classified as PAM50-defined basal-like subtype. Immunologically, sHR + /HER2- tumors had elevated tumor mutation burden (TMB), higher expression of immune checkpoint genes (e.g., PD-1, PD-L1, CTLA4), and greater infiltration by tumor-infiltrating lymphocytes (TILs), particularly CD8 + T cells, than dHR + /HER2- tumors.
CONCLUSION: Compared to dHR + /HER2- breast cancer, sHR + /HER2- cases showed a relative sensitivity to neoadjuvant chemotherapy but poorer prognosis. The immune-activated phenotype of sHR + /HER2- breast cancer indicates that it may benefit from immunotherapy approaches, but these findings warrant validation in prospective studies.

Keywords:  Early breast cancer; Hormone receptor-positive breast cancer; Immunotherapy; Neoadjuvant treatment

DOI:  https://doi.org/10.1007/s10549-025-07822-3
Arch Ital Urol Androl. 2025 Sep 17. 14264

Prognostic value of combined tumor regression grade and TNM stage in muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.

Manuel Lopes, José Pereira, Maria José Temido, João Gama, Edgar Silva, Vasco Quaresma, João Lorigo, Rui Pedrosa, João Pedroso Lima, Henrique Dinis, Lorenzo Marconi, Vítor Sousa, Arnaldo Figueiredo.

INTRODUCTION: Tumor regression grade (TRG) is a recognized prognostic marker in several solid tumors treated with neoadjuvant therapy, but its clinical relevance in muscle-invasive bladder cancer (MIBC) remains under investigation. This study aimed to evaluate the prognostic value of TRG and its integration with pathological TNM staging in patients with MIBC treated with neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC).
MATERIALS AND METHODS: We conducted a retrospective analysis of 51 patients with MIBC who received platinum-based NAC followed by RC and lymphadenectomy between 2013 and 2024. TRG was assessed according to the Fleischmann classification and combined with ypTNM stage to categorize patients as complete, partial or non-responders. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier analysis, and independent prognostic factors were identified through Cox regression models.
RESULTS: Complete response (ypT≤1, ypN0, TRG1) was observed in 43.1% of patients. Median OS was 19 months, with 3- and 5-year OS rates of 28.6% and 14.3%, respectively. Complete responders demonstrated significantly improved OS and DFS (p<0.001). On multivariable analysis, absence of nodal involvement (p=0.047) and complete response (p=0.012) were independently associated with better OS. Negative surgical margins showed a trend toward improved survival (p=0.064).
CONCLUSIONS: TRG is a reproducible and clinically meaningful histopathologic scoring system that enhances prognostic stratification when combined with pathological TNM staging. Its integration into routine post-NAC assessment may improve postoperative decision-making and help identify patients who could benefit from tailored surveillance or adjuvant strategies.

DOI: https://doi.org/10.4081/aiua.2025.14264
J Coll Physicians Surg Pak. 2025 Sep;35(9): 1128-1134

Postoperative CA-125 as a Prognostic Marker for Overall Survival in Ovarian Cancer.

Ahmet Burak Agaoglu, Ferhat Ekinci, Atike Pinar Erdogan, Mustafa Sahbazlar, Emine Turkmen.

OBJECTIVE: To investigate the association between postoperative CA-125 levels and overall survival (OS) in patients with ovarian cancer, assessing its potential role as a prognostic biomarker.
STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Medical Oncology, Faculty of Medicine, Celal Bayar University, Manisa, Turkiye, from February 2012 to November 2024.
METHODOLOGY: The medical records of 211 women diagnosed with ovarian cancer were retrospectively reviewed. Descriptive statistical analyses were conducted to investigate the relationship between CA-125 levels and OS. Patients were categorised into high and low perioperative CA-125 groups based on predefined cut-off values: 305 U/mL preoperatively and 30.4 U/mL postoperatively. The predictive performance of preoperative and postoperative CA-125 levels for ovarian cancer recurrence was assessed using receiver operating characteristic (ROC) analysis. The Kaplan-Meier survival curves were employed to estimate OS, and the Cox regression analysis was performed for univariate and multivariate assessments.
RESULTS: Significant differences in OS were observed between the patients with low versus high postoperative CA-125 levels: 1-year OS (93.3% vs. 81.8%), 3-year OS (87.8% vs. 48.1%), 5-year OS (73.3% vs. 35.4%), and 10-year OS (52.0% vs. 19.7%) (p <0.001). Furthermore, postoperative CA-125 levels were independent predictors of both OS (univariate: p <0.001; multivariate: p = 0.009) and progression-free survival (PFS) (univariate: p = 0.005; multivariate: p = 0.011).
CONCLUSION: Perioperative CA-125 levels hold significant prognostic value in ovarian cancer management, offering a valuable biomarker for predicting survival outcomes and disease progression.
KEY WORDS: Postoperative CA-125, Tumour marker, Ovarian cancer, Overall survival, Prognostic marker.

DOI: https://doi.org/10.29271/jcpsp.2025.09.1128
Immunotherapy. 2025 Sep 15. 1-19

Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.

Huiwen Zhang, Juwei Gao, Zipeng Zhang, Bo Zhang.

  With the rapid advancements in oncology, immunology, and molecular biology, immunotherapy has emerged as a cornerstone of anti-tumor treatment, complementing traditional modalities such as surgery, radiotherapy, and chemotherapy. Among the many immunotherapy strategies, adoptive cell therapy (ACT) is the most representative one. A key technology within ACT is chimeric antigen receptor (CAR) T-cell therapy, a precision-targeted treatment that leverages genetic engineering to modify T cells, enabling them to express antigen-specific receptors independent of major histocompatibility complex (MHC) restrictions. In recent years, continuous optimization of CAR-T therapy has been leading to remarkable clinical outcomes in oncology. However, its efficacy is significantly compromised by T-cell exhaustion, characterized by reduced proliferative capacity, attenuated anti-tumor activity, and limited persistence. Notably, CAR-T cell exhaustion is primarily driven by repeated tumor antigen stimulation, sustained autonomous activation of CAR constructs, and the immunosuppressive tumor microenvironment (TME), collectively contributing to disease relapse in hematologic malignancies and limited efficacy in solid tumors. Therefore, it is important to elucidate and inhibit the mechanism of CAR-T cell dysfunction to improve its efficacy. Overcoming these challenges will facilitate the development of CAR-T cells with sustained proliferative potential and tumor clearance.

Keywords:  CAR-T cell exhaustion; Chimeric antigen receptor T cells; adoptive cell therapy; cancer immunotherapy; tumor immune microenvironment

DOI:  https://doi.org/10.1080/1750743X.2025.2560798
Cancer Discov. 2025 Sep 19.

Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy.

Xiaojun Yan, Wenbin Xu, Han Yao, Zhen Wu, Jingyuan Ning, Shidong Zhao, Yajing Liu, Meng Zhang, Dongkui Xu, Zhanlong Shen, Wei Gu, Donglai Wang.

Although p53 plays a central role in tumor suppression, how it is regulated in T cells to exert antitumor effects remains unclear. Here, we show that activation of T cell-intrinsic p53 via carboxyl-terminal domain (CTD) acetylation during immunotherapy activates the IFN-γ pathway, promotes CD8+ T cell infiltration, and elicits CD8+ T cell-dependent antitumor immunity. Using T cell-specific knockin mouse models, we demonstrate that loss of CTD acetylation in T cells abrogates CD8+ T cell-dependent antitumor immunity whereas expression of CTD acetylation-mimicking p53 in T cells enhances this immune response. Moreover, we identify IFNG as a direct target of T cell-intrinsic p53 and uncover a positive feedback loop between p53 and the IFN-γ pathway for enhancing T cell-dependent antitumor immunity. Our study reveals that CTD acetylation-mediated activation of T cell-intrinsic p53 promotes antitumor immunity in response to immunotherapy, highlighting a non-tumor cell-autonomous mechanism of p53 action by regulating adoptive immune responses.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0649