bims-tuinly 2025-11-09 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–11–09
eighteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Spermidine Remodels the Mitochondrial Metabolism of Tumor-Infiltrating Lymphocytes.
Peptide-MHC-targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells.
CD103-Positive Tumor-Infiltrating Lymphocytes Predict a Favorable Prognosis in Colorectal Cancer with Liver Metastasis.
The transcription factor ZEB2 mediates the antitumor efficacy of tumor-infiltrating lymphocytes in non-small cell lung cancer.
Development and validation of prognostic model based on distribution and density of CD3+ and CD8+ infiltrating lymphocytes in breast cancer: A multicenter cohort study.
The antitumor mechanism of immuno-flap treatment in a rat model of head and neck cancer.
ICIs Exceptional Long Response in TNBC: Addressing the Issue of Optimal ICIs Duration. Two Cases and Review of the Literature.
Breast carcinoma tumour-infiltrating lymphocytes in pre- and post-systemic therapy in HIV-positive and HIV-negative women.
CD155-TIGIT/CD96/CD226 immune checkpoint axis interacting with tumor-infiltrating lymphocytes to exhibit diverse prognostic effects on breast cancer: a cohort study.
Metabolic modulation of CD8⁺ T cells by metformin: A promising adjuvant strategy for CD8⁺ T Cell-Based Immunotherapies.
Plasminogen Activator Inhibitor-1 Mediates Tolerance to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer.
Multiplex engineering and multifunction T cells for precise and effective immunotherapies.
Beyond CAR-T Cells: exploring CAR-NK, CAR-M, and CAR-γδ T strategies in solid tumor immunotherapy.
Harnessing IL-2 without feeding the enemy: modern strategies to overcome regulatory T cell expansion in cancer immunotherapy.
Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma.
Ex vivo expanded human regulatory T cells promote cholesterol efflux and PON1 expression in oxLDL-exposed macrophages via gap junction-mediated cAMP transfer.
Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer.
Establishment and validation of prognostic nomograms in female lung adenocarcinoma patients.

J Immunol Res. 2025 ;2025 7550012

Spermidine Remodels the Mitochondrial Metabolism of Tumor-Infiltrating Lymphocytes.

Yizhe Sun, Hao Fu, Xinyu Li, Meng Wan, Hongchao Xiong, Chaoting Zhang.

  Adoptive cell therapy (ACT) utilizing tumor-infiltrating lymphocytes (TILs) has significant potential in treating various cancers; however, its effectiveness is often compromised by the tendency of TILs to become exhausted and dysfunctional. Revitalizing these essential immune cells is crucial for amplifying their antitumor efficacy. Our study investigates the influence of spermidine on the metabolic pathways of TILs, focusing on its critical contribution to T cell vitality. We assessed the impact of spermidine on glucose absorption, mitochondrial functionality, and energy production in TILs. The application of spermidine resulted in a pronounced improvement in mitochondrial functionality and energy production, indicated by a surge in mitochondrial numbers and enhanced activity of the tricarboxylic acid (TCA) cycle. Importantly, the suppression of mitochondrial metabolism negated the beneficial effects of spermidine on mitigating exhaustion and enhancing cellular activity, highlighting the essential role of mitochondrial metabolism in the action of spermidine. Our research suggests that modulation of metabolism by spermidine could be a potential strategy to strengthen the antitumor capabilities of TIL-based treatments, offering a promising method to better manage solid tumors.

Keywords:  TCA cycle; metabolism; mitochondria; spermidine

DOI:  https://doi.org/10.1155/jimr/7550012
Sci Adv. 2025 Nov 07. 11(45): eadv2331

Peptide-MHC-targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells.

Ellen J K Xu, Blake E Smith, Winiffer D Conce Alberto, Michael J Walsh, Birkley Lim, Megan T Hoffman, Li Qiang, Ariana Barreiro, Emma N Finburgh, Jiayi Dong, Andrea Garmilla, Qingyang Henry Zhao, Caleb R Perez, Stephanie A Gaglione, Connor S Dobson, Michael Dougan, Stephanie K Dougan, Michael E Birnbaum.

Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate effective antitumor responses. Despite clinical promise, current TIL production protocols involve weeks-long ex vivo expansions that can affect treatment efficacy. Therefore, additional tools are needed to engineer TILs to have increased potency while mitigating manufacturing challenges. Here, we present a strategy for pseudotyping retroviruses with peptide-major histocompatibility complexes (pMHCs) for antigen-specific gene delivery to CD8 T cells and validate therapeutic impact in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses specifically deliver function-enhancing cargos while simultaneously activating and expanding antitumor T cells. This targeting precision enables in vivo engineering of tumor-specific T cells, resulting in improved overall survival in B16F10-bearing mice. Together, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific T cells directly in vivo, with the potential to substantially streamline engineered cell therapy production.

DOI: https://doi.org/10.1126/sciadv.adv2331
Ann Surg Oncol. 2025 Nov 06.

CD103-Positive Tumor-Infiltrating Lymphocytes Predict a Favorable Prognosis in Colorectal Cancer with Liver Metastasis.

Yuanhui Wu, Yumo Xie, Jinxin Lin, Ji Cui, Hui Yang, Maram Alenzi, Pinzhu Huang, Anpei Huang, Meijin Huang.

   BACKGROUND: High infiltration of CD103+ tumor infiltrating lymphocytes (TILs) is associated with improved patient survival in colorectal cancer. However, the spatial distribution and clinical significance of CD103+ TILs in colorectal liver metastasis (CRLM) remain unclear.
METHODS: This study enrolled 84 patients with CRLM who underwent simultaneous surgical resection of both primary colorectal tumors (PT) and liver metastases (LM). The abundance of CD103+ TILs in different intratumoral compartments were evaluated using immunohistochemistry. Additionally, multiplex immunofluorescence analysis was performed to assess CD103+ TIL subsets. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic analysis were performed to investigate the functional differences of CD103+CD8+ T cells between PT and LM using a published dataset.
RESULTS: The presence of CD103+ TILs in PT did not correlate with the prognosis of patients with CRLM. Conversely, an increased infiltration of CD103+ TILs in LM was associated with improved survival outcomes. Notably, CD103+ TILs in the stromal compartments of the tumor center of LM emerged as an independent prognostic factor for CRLM patients. The majority of CD103+ TILs in CRLM tissues were identified as CD8+CD103+ cells, followed by CD4+CD103+ cells. scRNA-seq analysis showed that the CD103+CD8+ T cells in the PT exhibit characteristics typical of CD8+ cytotoxic T cells, while those in the LM display features of tissue-resident memory T cells.
CONCLUSIONS: These findings reveal the heterogeneity in the spatial distribution of CD103+ TILs within both PT and LM tissues. Notably, the infiltration of CD103+ TILs in LM serves as a prognostic biomarker for CRLM patients.

Keywords:  CD103+ TILs; Colorectal liver metastasis; Intratumor compartment; Prognosis; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1245/s10434-025-17977-4
Cell Death Dis. 2025 Nov 07. 16(1): 806

The transcription factor ZEB2 mediates the antitumor efficacy of tumor-infiltrating lymphocytes in non-small cell lung cancer.

Jiajia Wang, Fei Liu, Yongyong Li, Jiaojiao Gao, Shasha Yang, Mei Tian, Lili Deng, Yan Yang, Beilei Gong, Chengling Zhao, Huiyuan Gong, Zongyu Xie, Yongchun Zhou, Rongzhong Huang, Qiang Luo, Depeng Jiang, Xiaojing Wang.

Immune checkpoint blockade (ICB) offers an in vivo approach to activate CD8+ tumor-infiltrating lymphocytes (CD8+TILs) in cases of advanced non-small cell lung cancer (NSCLC). A large fraction of NSCLC patients is unresponsive to ICBs and relapse due to the development of dysfunctional CD8+TILs with impaired cytotoxicity. Therefore, an improved understanding of regulator(s) that favor the development of cytotoxic Teff cells over dysfunctional CD8+TILs is required for the success of ICB therapy in NSCLC patients. Here, our metaVIPER-based scRNA-seq analysis of deep CD8+ cell scRNA-seq data from 14 treatment-naïve NSCLC patients revealed that the master regulon ZEB2 may drive CD8+ differentiation along the cytotoxic effector trajectory in NSCLC tumors. In vitro, ZEB2 acts downstream of T-bet to stimulate lung tumor-reactive Teff cell differentiation. This T-bet/ZEB2 axis displays immunotherapeutic effects on KP.SIY lung tumors independent of ICB therapy and mediates the therapeutic effects of murine serum albumin-fused IL-2 + IL-12 combination immunotherapy (IL2-MSA + IL12-MSA) in mice. IL2-MSA + IL12-MSA operates through a parallel STAT4/FOXO1-mediated mechanism that promotes CD8+TIL T-bet/ZEB2 expression and lung tumor-reactive Teff cell differentiation. In conclusion, immunotherapeutic regimens that support ZEB2 activity in CD8+ cells may show promise in NSCLC patients.

DOI: https://doi.org/10.1038/s41419-025-08112-y
Breast. 2025 Oct 24. pii: S0960-9776(25)00649-6. [Epub ahead of print]84 104632

Development and validation of prognostic model based on distribution and density of CD3+ and CD8+ infiltrating lymphocytes in breast cancer: A multicenter cohort study.

Xu Zhang, Zheng Wang, Yiwei Tong, Xi Sun, Weiqi Gao, Xiaocun Fei, Yujie Tang, Juanying Zhu, Zhi'an Li, Kunwei Shen, Xiaosong Chen.

   BACKGROUND: The prognostic value of infiltrating lymphocytes distribution and their densities in breast cancer is unknown. This study aimed to develop a tumor immune microenvironment-based model to predict prognosis in early breast cancer patients.
METHODS: Densities of CD3+ and CD8+ lymphocytes in the core of tumor (CT) and invasive margin (IM) regions were quantified. A combined score of CD3+ and CD8+ infiltrating lymphocytes in both CT and IM regions was performed to construct the prognostic immunoindex (PII) as follows, low-PII (score 0), intermediate-PII (score 1 to 2), and high-PII (score 3 to 4). The PII was developed in the training cohort and verified in the internal and external validation cohorts.
RESULTS: A total of 1194 patients were included. In the training cohort, a higher 5-year DFS was observed in the high- or intermediate-PII groups compared with the low-PII group (95.1 %, 89.1 %, 83.7 %, respectively, P = 0.008). Patients with a high PII also had the best 5-year OS of 97.5 %, compared to 96.4 % and 92.7 % in the intermediate- and low-PII groups (P = 0.016), which was also found in the internal (P = 0.011 for DFS, P = 0.013 for OS) and external validation cohort (P = 0.010 for DFS, P = 0.143 for OS). PII was shown to be an independent favorable prognostic factor for DFS (P < 0.001) and OS (P = 0.001), especially in HER2-positive (P = 0.009) and triple-negative (P = 0.007) breast cancer patients.
CONCLUSION: The PII model can predict survival in breast cancer patients, which might provide a novel risk classification to guide further individualized treatment.

Keywords:  Breast cancer; Immunoindex; Prognosis; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.breast.2025.104632
Cancer Immunol Immunother. 2025 Nov 03. 74(12): 355

The antitumor mechanism of immuno-flap treatment in a rat model of head and neck cancer.

Hiroaki Mori, Yasuto Akiyama, Chie Maeda, Akari Kanematsu, Tadashi Ashizawa, Kazue Yamashita, Haruo Miyata, Akira Iizuka, Tomoatsu Ikeya, Yoshichika Yasunaga, Jun Araki.

   BACKGROUND: Local recurrence after surgical resection is a major clinical challenge in patients with advanced head and neck cancer (HNC). We previously reported using transfer of a flap treated with dendritic cells (DCs) ("immuno-flap") as a novel cancer immunotherapy in a rat model of HNC. However, several problems, such as the improvement of DC yield and the verification of DC tracking, remained to be solved.
METHODS: The initial DC production protocol was revisited, and the specific mechanism of the antitumor effect associated with functional DCs was investigated.
RESULTS: The yield and the purity of potent DCs were improved, and an in vivo tracking experiment revealed that, when injected into the skin flap, the DCs migrated to local lymph nodes within 24 h. In an in vivo long-term protection model in which DCs were injected into the skin flap weekly for 4 weeks, no strong antitumor effect on HNC tumor progression was observed, but a remarkable pathological effect was verified. Moreover, an enzyme-linked immunospot assay demonstrated that more CD8+ T cells positive for PD-1, CD40LIG, and TNF-α expression and producing interferon γ specific to SCC-158 tumor cells were identified in tumors and spleens from rats treated using immuno-flaps.
CONCLUSIONS: These results indicate that immuno-flap transfer to prevent local recurrence in patients with HNC has potential for clinical application given the improved yield and quality of antitumor DCs.

Keywords:  Dendritic cell; Enzyme-linked immunospot assay; Head and neck cancer; Immuno-flap; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s00262-025-04208-8
Cancer Rep (Hoboken). 2025 Nov;8(11): e70397

ICIs Exceptional Long Response in TNBC: Addressing the Issue of Optimal ICIs Duration. Two Cases and Review of the Literature.

Simone Rota, Carolina Sciortino, Silvia Damian, Matteo Duca, Giorgia Villa, Matteo De Monte, Elisabella Ebrahem, Laura Cattaneo, Chiara Volpi, Alessandra Casale, Diletta Sorrentino, Sara Pessina, Antonia Martinetti, Filippo De Braud, Sara Cresta.

   BACKGROUND: Breast cancer is the leading cause of cancer-related mortality in women, with triple-negative breast cancer (TNBC) being an aggressive subtype associated with poor prognosis and limited treatment options. TNBC is known for its immunogenic characteristics, including high genetic instability and elevated tumor-infiltrating lymphocytes (TILs). Immune checkpoint inhibitors (ICIs) have shown efficacy in TNBC treatment, but the optimal treatment duration in case of prolonged response remains unclear.
CASE: This case series here reported presents two patients with metastatic TNBC who demonstrated an excellent response to ICI therapy. The first patient, a 60-year-old, was enrolled in a Phase I clinical trial and received a combination of anti-PD-1, anti-LAG-3, and anti-CSF-1 monoclonal antibodies. The second patient, a 45-year-old with BRCA1-mutated TNBC, participated in a Phase II trial and received a combination of avelumab (anti-PD-L1) and talazoparib (PARP inhibitor). Both patients achieved a complete radiological response (CR), which has been maintained for 5 years. A literature review performed here identified seven additional long-term ICI responders in metastatic TNBC. While ICIs showed significant efficacy in some patients, variability in PD-L1 expression and TILs suggests that other factors may influence response. Two patients in previous studies discontinued ICIs after 2 years without progression, prompting questions about the optimal treatment duration.
CONCLUSION: ICIs optimal treatment duration remains uncertain. Literature on metastatic melanoma suggests that discontinuing ICIs after a complete response rarely leads to recurrence. Prospective studies and emerging biomarkers, such as circulating tumor DNA, may help tailor treatment decisions.

Keywords:  breast cancer; immune checkpoint inhibitors; immunotherapy; systemic anticancer treatment; triple negative breast cancer

DOI:  https://doi.org/10.1002/cnr2.70397
South Afr J HIV Med. 2025 ;26(1): 1741

Breast carcinoma tumour-infiltrating lymphocytes in pre- and post-systemic therapy in HIV-positive and HIV-negative women.

Mishka Adam, Jenny Edge, Louis J de Jager.

   Background: HIV-positive women with breast cancer do not exhibit significant differences in tumour characteristics when compared to their HIV-negative counterparts. Stromal tumour-infiltrating lymphocytes (TILs) serve as an important indicator of the host's capacity to combat malignancy, particularly during the early stages of tumour progression.
Objectives: The objective of this study was to assess and compare the pathological characteristics of breast carcinomas, specifically focusing on TILs in histological specimens obtained before and after systemic therapy, between HIV-positive and HIV-negative patient groups at a public hospital in the Western Cape province. Additionally, the study aimed to determine whether a higher percentage of TILs was associated with a favourable treatment response.
Method: A retrospective cohort study was conducted, incorporating a negative control group matched for histological subtype, and intrinsic subtypes among patients diagnosed between January 2017 and December 2018.
Results: There was no significant difference in TILs before and after treatment, nor was there a difference between patients treated with neoadjuvant chemotherapy (NACT) compared to those receiving endocrine therapy (ET) within both groups. A complete pathological response was achieved in four HIV-positive patients (14%) and one HIV-negative patient (2%). An inversely proportional relationship was noted between TILs and CD4 counts prior to treatment.
Conclusion: This study found no significant differences in TILs between HIV-positive and HIV-negative women with breast cancer. There is a need for further research on the prognostic value of TILs, especially for guiding additional treatment options including the use of immune checkpoint inhibitors.

Keywords:  HIV; RCB index; South Africa; TILs; women with breast carcinoma

DOI:  https://doi.org/10.4102/sajhivmed.v26i1.1741
Front Immunol. 2025 ;16 1649078

CD155-TIGIT/CD96/CD226 immune checkpoint axis interacting with tumor-infiltrating lymphocytes to exhibit diverse prognostic effects on breast cancer: a cohort study.

Xin Ou, Junyu Yin, Feng Shi, Yanjie Zhao, Quan Zhou, Keyu Yuan, Shuzhen Lyu, Jiangping Wu, Yanping Li, Qingkun Song.

   Background: CD155, an immune checkpoint molecule interacted with receptors of TIGIT/CD96/CD226 to exhibit co-inhibitory and co-stimulatory modulation on tumor immune microenvironment. Nevertheless, the exploration of collectively prognostic effect of these four molecules on breast cancer (BC) was limited. This study aimed to investigate the prognosis effect of CD155-TIGIT/CD96/CD226 complex in BC.
Methods: CD155-TIGIT/CD96/CD226 expression was evaluated by immunohistochemistry in tumor microenvironment (TME) by pathological professionals and the associations with clinical characteristics and prognosis were investigated under a cohort study design.
Results: CD155 was detected on TME tumor cells (TC) and TIGIT/CD96/CD226 were detected on both TC and stromal tumor-infiltrated lymphocytes (TILs). The four molecules showed significant correlation with clinicopathological characteristics and prognosis. High CD155 was associated with relapse (HR = 2.21, 95%CI:1.18-4.13) and death (HR = 2.57, 95%CI:1.29-5.10). High expression of CD226 (HR = 1.79, 95%CI:1.03-3.11) and CD96 (HR = 2.65, 95%CI:1.09-6.44) on TC was correlated with high risk of relapse. High expression of TIGIT on TILs was related to poor prognosis of relapse (HR = 2.06, 95%CI:1.02-4.14), while the expression on TC was a protective factor for relapse (HR = 0.45, 95%CI:0.24-0.83) and death (HR = 0.32, 95%CI:0.16-0.66). Additionally, tumoral and stromal expression of these biomarkers interacted with TME infiltration of stromal TILs to exhibit the diverse prognosis effect.
Conclusion: The CD155-CD226/TIGIT/CD96 immune checkpoint complex expressed on both TME TC and TILs, and interacted with TILs to exhibit diverse prognosis effect on BC. The immunotherapy against these checkpoint proteins should check the expression on both TC and TILs and further studies should explore the molecule complex collectively for comprehensive prediction of BC prognosis.

Keywords:  CD155-TIGIT/CD226/CD96 immune checkpoint molecules; breast cancer; prognosis; tumor cells; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2025.1649078
Pharmacol Res. 2025 Oct 30. pii: S1043-6618(25)00440-2. [Epub ahead of print]222 108015

Metabolic modulation of CD8⁺ T cells by metformin: A promising adjuvant strategy for CD8⁺ T Cell-Based Immunotherapies.

Quynh Chau Ton Nu, Pil-Hoon Park.

  CD8⁺ T cells play a pivotal role in immune defense through their cytotoxic activity. However, persistent antigen exposure and immunosuppressive microenvironments drive CD8⁺ T cells into a dysfunctional or exhausted state, thereby limiting the effectiveness of CD8⁺ T cell-based immunotherapies. Increasing evidence indicates that CD8+ T cell activation and effector functions are tightly coupled to dynamic metabolic reprogramming that sustains the energetic and biosynthetic requirements for effective immune responses. Metformin, beyond its established role as an antidiabetic medication, demonstrates considerable promise as an immune-metabolic adjuvant capable of enhancing the efficacy of CD8⁺ T cell-based immunotherapies and reshaping immune responses across various pathological conditions. In this review, we provide a comprehensive overview of the current insights into the metabolic and functional regulation of CD8⁺ T cells by metformin in a context-dependent manner, with an emphasis on its therapeutic potential as an immunotherapeutic adjuvant. We also highlight the translational opportunities and challenges associated with the clinical integration of metformin and propose strategies to overcome context-specific barriers to its clinical application.

Keywords:  CD8(+) T cell; Immunotherapy; Metabolic programming; Metformin

DOI:  https://doi.org/10.1016/j.phrs.2025.108015
Mol Cancer Ther. 2025 Nov 06.

Plasminogen Activator Inhibitor-1 Mediates Tolerance to Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer.

Masahiko Sumii, Takeshi Masuda, Kiyofumi Shimoji, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Yasushi Horimasu, Takahiro Mimae, Taku Nakashima, Hiroshi Iwamoto, Yoshihiro Miyata, Hironobu Hamada, Morihito Okada, Toshio Miyata, Noboru Hattori.

Immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with non-small-cell lung cancer (NSCLC), but the cure rate remains low because tolerant persister cancer cells can survive within the tumor during ICI treatment. We have previously reported that plasminogen activator inhibitor-1 (PAI-1) is involved in tolerance acquisition to osimertinib in epidermal growth factor receptor-mutated NSCLC. This study aimed to examine the role of PAI-1 in ICI tolerance and whether PAI-1 may be a therapeutic target to overcome this tolerance. In a mouse subcutaneous tumor model using Lewis lung carcinoma or KLN205 cells, cancer cells surviving within the tumor 7 days after anti-programmed death-1 (aPD-1) antibody treatment were defined as aPD-1 antibody-tolerant persister cells (aPD-1-TPs). PAI-1 and mesenchymal gene expression levels were higher in aPD-1-TPs than in control cells. Immunohistochemical analyses showed higher numbers of tumor-associated macrophages (TAMs), expression of programmed death-ligand 1 (PD-L1) in cancer cells, and degree of angiogenesis. In contrast, the number of tumor-infiltrating lymphocytes (TILs) was lower in aPD-1 antibody-tolerant tumors than in control tumors. Combination treatment with an aPD-1 antibody and the PAI-1 inhibitor TM5614 decreased mesenchymal gene expression, PD-L1 expression, TAM numbers, and angiogenesis and increased TIL counts in tolerant tumors. Furthermore, it resulted in prolonged inhibition of tumor growth. In conclusion, this study underscores the involvement of PAI-1 in the survival of aPD-1-TPs via epithelial-mesenchymal transition and alteration of the tumor microenvironment. Combination treatment with an aPD-1 antibody and TM5614 can be a new therapeutic strategy for NSCLC.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0890
Front Immunol. 2025 ;16 1680410

Multiplex engineering and multifunction T cells for precise and effective immunotherapies.

Leila Jafarzadeh, Ali Smaani, Jean-Sébastien Delisle.

  Adoptive T cell transfer has emerged as a pillar of modern cancer immunotherapy. Propelled by viral and non-viral-based technologies, such as CRISPR-Cas9, genetic engineering offers novel opportunities for both emerging cellular therapies and the improvement of more established approaches such as chimeric antigen receptor (CAR) modified T cells. First-generation genetically modified T-cell therapeutics remain limited by the intrinsic constraints imposed by T-cell biology, such as T-cell exhaustion, poor trafficking into hostile tumor beds, toxicity, and challenges associated with tumor antigenic escape. Several of such limitations can be addressed by further engineering, expanding significantly the potential of cell therapy. This review focuses on the promise of using currently available cellular engineering technologies to genetically engineer single T cells at multiple different loci and/or confer several novel functions to circumvent the shortcomings of adoptive immunotherapy to treat cancer. Various methodologies and rationales for the design of these advanced engineered cellular products are described, along with emerging clinical data supporting the use of multiplex-engineered T cells. The limitations of advanced cell engineering and the remaining gaps that need to be filled to optimize the efficacy of adoptive T-cell immunotherapies are also discussed.

Keywords:  CRISPR-Cas9; T cells; Transgenic TCR; adoptive immunotherapy; cancer immunotherapy; chimeric antigen receptor; genetic engineering

DOI:  https://doi.org/10.3389/fimmu.2025.1680410
Front Immunol. 2025 ;16 1675807

Beyond CAR-T Cells: exploring CAR-NK, CAR-M, and CAR-γδ T strategies in solid tumor immunotherapy.

Yingjie Hou, Shihua Hu, Chong Liu, Xin Chen, Yuru Wang, Youzherui Li, Zihe Fu, Chunjing Feng, Yanhua Gong, Zichuan Liu, Shouchun Peng.

  Adoptive cell therapy (ACT) employing chimeric antigen receptor (CAR) engineering represents a transformative advancement in cancer immunotherapy. CAR-T cell therapies have demonstrated significant clinical success in hematological malignancies, yet their application to solid tumors faces persistent challenges. Key limitations include the paucity of tumor-specific antigens, poor intratumoral infiltration, immunosuppressive tumor microenvironment (TME), and treatment-related toxicities such as cytokine release syndrome (CRS) and neurotoxicity. In contrast, CAR natural killer (CAR-NK) cells show promise in solid tumors such as ovarian, pancreatic, and glioblastoma, with encouraging preclinical and early clinical evidence, although limited persistence and antigen heterogeneity remain major challenges. Unlike CAR-T cells, CAR-NK therapies mediate tumor clearance through both cytotoxic (e.g., granzyme/perforin release) and cytokine-mediated mechanisms while mitigating toxicity risks. Their lack of human leukocyte antigen (HLA) dependency enables "off-the-shelf" manufacturing from allogeneic donors, circumventing patient-specific production bottlenecks. CAR-macrophage (CAR-M) therapies further address solid tumor barriers by leveraging innate phagocytic clearance, antigen-presenting functions, and TME penetration. Macrophages inherently infiltrate hypoxic tumor regions and remodel stromal barriers, enabling CAR-Ms to synergize with adaptive immunity by cross-priming T cells. Preclinical models highlight CAR-M efficacy in depleting immunosuppressive tumor-associated macrophages (TAMs) and reversing TME-driven immune evasion. Emerging CAR- Gamma-Delta T (CAR-γδ T) cell therapies combine CAR-mediated antigen specificity with the intrinsic tumoricidal activity of γδ T cells, which recognize stress-induced ligands independently of major histocompatibility complex (MHC) presentation. This dual-targeting capability enhances tumor selectivity while reducing on-target/off-tumor toxicity. This review systematically examines cellular sources, mechanistic advantages and clinical progress. By evaluating these platforms' complementary strengths, we propose rational strategies for integrating CAR-NK, CAR-M, and CAR-γδ T cells into tailored therapeutic regimens for solid tumors.

Keywords:  NK cells; chimeric antigen receptor; macrophage cells; solid tumor; γδT cells

DOI:  https://doi.org/10.3389/fimmu.2025.1675807
Cancer Lett. 2025 Nov 01. pii: S0304-3835(25)00681-0. [Epub ahead of print] 218109

Harnessing IL-2 without feeding the enemy: modern strategies to overcome regulatory T cell expansion in cancer immunotherapy.

Wenxue Ma, Catriona Jamieson.

DOI: https://doi.org/10.1016/j.canlet.2025.218109
Immunity. 2025 Nov 03. pii: S1074-7613(25)00434-0. [Epub ahead of print]

Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma.

Annabell Bachem, Michele Clarke, Geraldine Kong, Ilaryia Tarasova, Lachlan Dryburgh, Lindsay Kosack, Ariane R Lee, Lewis D Newland, Teagan Wagner, Emma Bawden, Kah Min Yap, Michael D Wilson, Sven Engel, Kayla R Wilson, Brendan E Russ, Kshitij Tandon, Peter Kar Han Lau, Grant McArthur, Vanessa R Marcelino, Paul A Beavis, Stephen J Turner, Jason Waithman, Timothy P Stinear, Shahneen Sandhu, Jan Schröder, Thomas Gebhardt, Sammy Bedoui.

  A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8+ T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127+CD8+ T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127+CD8+ T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8+ T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8+ T cells.

Keywords:  CD8 T cells; SCFAs; butyrate; melanoma; metabolism; microbiome; microbiota; stemness

DOI:  https://doi.org/10.1016/j.immuni.2025.10.004
Front Immunol. 2025 ;16 1662925

Ex vivo expanded human regulatory T cells promote cholesterol efflux and PON1 expression in oxLDL-exposed macrophages via gap junction-mediated cAMP transfer.

Caraugh Jane Albany, Daniela Mastronicola, Momchil Popov, Wladislaw Stroukov, Anthony S Wierzbicki, Rocio Teresa Martinez-Nunez, Giovanna Lombardi, Cristiano Scottà.

  Lipid-driven inflammation contributes to the development of atherosclerosis, and regulatory T cells (Tregs) have been proposed to influence macrophage responses to lipid stress. While adoptive Treg transfer has been shown to be safe in clinical studies, the mechanisms by which Tregs modulate macrophage lipid handling remain incompletely understood. In this study, we investigated the effects of ex vivo-expanded human Tregs on primary monocyte-derived M2-like macrophages exposed to oxidized low-density lipoprotein (oxLDL) in an in vitro coculture system. We assessed macrophage phenotype, gene expression, and cholesterol accumulation using flow cytometry, RNA sequencing, and western blotting. Our data show that coculture with Tregs attenuated oxLDL-induced pro-inflammatory responses and reduced intracellular lipid accumulation in macrophages. Mechanistically, we found evidence that Tregs transfer cyclic AMP (cAMP) into macrophages, which enhanced the ABCA1-mediated cholesterol efflux pathway and increased expression of paraoxonase-1 (PON1). These findings provide mechanistic insight into how Tregs modulate macrophage responses to oxLDL under controlled in vitro conditions. They highlight potential pathways through which Tregs may regulate macrophage lipid metabolism and inflammatory activity. Further in vivo studies will be essential to determine the physiological significance and therapeutic potential of these mechanisms.

Keywords:  atherosclerosis; cholesterol; macrophages; paraxonase-1; regulatory T (Treg) cells

DOI:  https://doi.org/10.3389/fimmu.2025.1662925
Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00449-0. [Epub ahead of print]

Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer.

Qianqian Gao, Xinnan Ling, Leen Liao, Fei Tang, Yujia Jiang, Shishang Qin, Wenhong Hou, Wei Zhou, Lijuan Jiang, Chunman Xiao, Yufei Bo, Yuhui Miao, Hai-Xi Sun, Ruoyao Wang, Kezhuo Yu, Qiaoqi Sui, Shijie Hao, Weijian Mei, Dongfang Wang, Xiuqing Zhang, Sijin Cheng, Linnan Zhu, Peirong Ding, Zemin Zhang.

  Total neoadjuvant therapy (TNT) is a standard care for locally advanced rectal cancer (LARC), yet the immune remodeling mechanisms underlying its efficacy remain unclear. Using single-cell RNA, T cell receptor, and spatial transcriptome sequencing of matched pre- and post-treatment samples, we depicted the tumor microenvironment (TME) dynamics induced by different neoadjuvant therapies. TNT is associated with reduced regulatory T cells and increased IFNG+CD8+ effector memory T cells with high IFNG expression, potentially contributing to improved complete response rates. The abundance of tumor-infiltrating CD8+ T cells is correlated with the enrichment of the ACKR1+ endothelial subset after TNT. We further validated that endothelial cells (ECs), when stimulated by IFNγ, potentially released by CD8+ T cells, acquire an enhanced ability for presenting antigens and activating CD8+ T cells. Together, our study systematically characterizes the TME dynamics and uncovers the unique interaction between activated CD8+ T cells and ECs after TNT.

Keywords:  CD8(+) T cells; IFNγ; endothelial cells; feedback loop; neoadjuvant chemoradiotherapy; rectal cancer; total neoadjuvant therapy

DOI:  https://doi.org/10.1016/j.ccell.2025.10.008
Medicine (Baltimore). 2025 Oct 17. 104(42): e45170

Establishment and validation of prognostic nomograms in female lung adenocarcinoma patients.

Feiyang Li, Fang Li, Dong Zhao, Haowei Lu.

  The incidence of lung adenocarcinoma in women is gradually increasing, but the prognostic factors affecting this group of patients have not been systematically studied, so we hope that we can construct a prognostic prediction model for this group of patients to provide a more accurate survival prediction. We performed a retrospective analysis of female patients with pathologically diagnosed lung adenocarcinoma, constructed nomograms of overall survival (OS) and cancer-specific survival (CSS) at 1, 3, and 5 years using COX regression analyses, and evaluated the prediction using the consistency index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) model performance with internal and external validation. We included a total of 11,562 patients, which were divided into 2 groups in a ratio of 7:3 Analysis using the chi-square test revealed that there was no statistically significant difference in the baseline information between the 2 data groups (P > .05). Age, race, marital status, AJCC stage, surgery, radiotherapy, chemotherapy, and distant metastasis were found to be influential factors for OS using COX regression analysis, and we used these influences to construct prognostic nomograms for OS. The same method was then used to screen the independent prognostic influences affecting CSS were age, marital status, AJCC stage, surgery, radiotherapy, chemotherapy, and distant metastasis, and prognostic nomograms for CSS were constructed using these factors. The prognostic models for OS and CSS were validated using ROC curves, C-indexes, correction curves, and DCA curves after the construction was completed, proving the accuracy and reliability of our models. This prediction model can more accurately predict the prognosis of female lung adenocarcinoma patients.

Keywords:  SEER database; lung adenocarcinoma; nomograms; predictive modeling; women

DOI:  https://doi.org/10.1097/MD.0000000000045170