Journal Articles

Coordinated immune activation following KRAS inhibition in syngeneic models reveals molecular pathways that potentiate and limit antitumor immunity Spotlight 

(1) Lu DR (2) Osgood T (3) Ma S (4) Zhang H (5) Kanke M (6) Tan JA (7) Paudel SN (8) Zhou H (9) Estrada J (10) Yamawaki T (11) Tarbell K (12) Rex K (13) DeVoss J (14) Martin S (15) Wang S (16) Canon J (17) Lipford JR (18) Coxon A (19) Li CM

Cancer immunology research

Lu et al. profiled the cellular changes after KRAS(G12C) and MEK inhibition, and demonstrated that these treatments drove distinct neoplastic cell fates and immune responses in a CT26 KRASG12C tumor model. KRAS(G12C)i induced a cDC1-driven mature cDC state via tumor, endothelial, and fibroblast signaling, increased CD8+ T cell clonal expansion, and promoted anti-inflammatory macrophage polarization, while MEKi induced limited clonal expansion and anti-inflammatory macrophages. KRAS(G12C)i plus anti-PD-1 expanded effector T cells and increased T cell clonal persistence, proinflammatory macrophage states, and mediators of antitumor immunity.

Contributed by Shishir Pant

(1) Lu DR (2) Osgood T (3) Ma S (4) Zhang H (5) Kanke M (6) Tan JA (7) Paudel SN (8) Zhou H (9) Estrada J (10) Yamawaki T (11) Tarbell K (12) Rex K (13) DeVoss J (14) Martin S (15) Wang S (16) Canon J (17) Lipford JR (18) Coxon A (19) Li CM

Cancer immunology research

Lu et al. profiled the cellular changes after KRAS(G12C) and MEK inhibition, and demonstrated that these treatments drove distinct neoplastic cell fates and immune responses in a CT26 KRASG12C tumor model. KRAS(G12C)i induced a cDC1-driven mature cDC state via tumor, endothelial, and fibroblast signaling, increased CD8+ T cell clonal expansion, and promoted anti-inflammatory macrophage polarization, while MEKi induced limited clonal expansion and anti-inflammatory macrophages. KRAS(G12C)i plus anti-PD-1 expanded effector T cells and increased T cell clonal persistence, proinflammatory macrophage states, and mediators of antitumor immunity.

Contributed by Shishir Pant

ABSTRACT: While mutant-specific KRAS inhibitors are approved to treat cancer, a deeper understanding of intratumoral changes driven specifically by KRAS inhibition is needed to maximize therapeutic responses. Here, we used single-cell RNA-seq, flow cytometry, and spatial transcriptomics to distinguish mechanisms of tumor control after KRASG12C inhibition (KRAS(G12C)i) or MEK inhibition (MEKi). Despite both inhibiting the MAPK pathway, KRAS(G12C)i and MEKi drive the adaptation of distinct neoplastic cell fates affecting metabolism and cell cycle regulation, and additive tumor suppression is observed after co-administration. KRAS(G12C)i results in the emergence of a specific, cDC1-driven mature conventional dendritic cell (cDC) state. Co-culture of treated neoplastic cells with cDC1s is sufficient to upregulate maturation markers such as CCR7, intercellular communication analyses suggest activation is augmented through non-immune mediators. Both KRAS(G12C)i and MEKi increase infiltration of cytotoxic T cells, but MEKi, which also targets non-malignant cells, is associated with a reduced capacity for T-cell proliferation and degranulation, consistent with distinct adaptive immune activation mechanisms. We observe that combination treatment of KRAS(G12C)i with anti-PD-1 immunotherapy further expands effector T-cell states, increases clonal persistence, and induces pro-inflammatory macrophages associated with higher overall survival that were largely absent after KRAS(G12C)i alone. Furthermore, combination treatment enhances intercellular communication networks among non-PD-1+ expressing cells that can perpetuate cDC activation. Our findings delineate distinct tumor and immune responses to KRAS and MEK inhibition and identify molecular features of the responding tumor microenvironment that may be leveraged to improve therapeutic efficacy.

Author Info: (1) Amgen Inc. South San Francisco, CA United States. (2) Amgen Inc. Thousand Oaks, CA United States. (3) Amgen Inc. South San Francisco, CA United States. (4) Amgen Inc. South San

Author Info: (1) Amgen Inc. South San Francisco, CA United States. (2) Amgen Inc. Thousand Oaks, CA United States. (3) Amgen Inc. South San Francisco, CA United States. (4) Amgen Inc. South San Francisco, CA United States. (5) Amgen (United States) South San Franciso United States. ROR: https://ror.org/03g03ge92 (6) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (7) Amgen Inc. Thousand Oaks, CA United States. (8) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (9) Amgen Inc. Thousand Oaks, CA United States. (10) Amgen Inc. South San Francisco, CA United States. (11) Amgen Inc. South San Francisco, CA United States. (12) Amgen Inc. Thousand Oaks, CA United States. (13) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (14) Amgen Inc. South San Francisco, CA United States. (15) Amgen Inc. South San Francisco, CA United States. (16) Amgen Inc. Thousand Oaks, CA United States. (17) Amgen (United States) United States. ROR: https://ror.org/03g03ge92 (18) Amgen Inc. Thousand Oaks, CA United States. (19) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92

Citation: Cancer Immunol Res 2026 Jul 3 Epub07/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397029

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Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer

Spotlight 

Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

Nature communications

To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

Contributed by Lauren Hitchings

Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

Nature communications

To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

Contributed by Lauren Hitchings

ABSTRACT: Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.

Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3

Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3) Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (4) Department of Investigative Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA (5) Institute for Applied Science and TRACTION platform, University of Texas MD Anderson Cancer Center, Houston, TX, USA (6) Department of Bioengineering, Rice University, Houston, TX, USA (7) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA (8) Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

Citation: Nat com 2026

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mRNA lipid nanoparticle cancer vaccine platform delivering multiple STING activators for enhanced antitumor activity Spotlight 

(1) Zeng Y (2) Xu J (3) Wang J (4) Xue L (5) Liu J (6) Geisler HC (7) Ma X (8) Melamed JR (9) Shi Q (10) Padilla MS (11) Luo Z (12) Zhu J (13) Thatte AS (14) Figueroa-Espada CG (15) Ang MJY (16) Murray AM (17) Yamagata HM (18) Kim D (19) Metzloff AE (20) Weissman D (21) Mitchell MJ

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Zeng, Xu, and Wang et al. developed an optimized cancer vaccine platform comprising a novel LNP co-encapsulating tumor antigen mRNA and two STING agonists. In primary BM-DCs, vaccination synergistically boosted CD80/CD86 expression and IFN-I secretion, and in mice, it enhanced antigen cross-presentation in spleens and tdLNs to induce antigen-specific CD8+ cytotoxic and memory T cell expansion. In tumor models, i.v. vaccine delivery inhibited s.c. tumor growth and vascularization. Vaccination upregulated gene sets for apoptosis and antigen processing, and reprogrammed immunosuppressive TAMs to a proinflammatory phenotype.

Contributed by Paula Hochman

(1) Zeng Y (2) Xu J (3) Wang J (4) Xue L (5) Liu J (6) Geisler HC (7) Ma X (8) Melamed JR (9) Shi Q (10) Padilla MS (11) Luo Z (12) Zhu J (13) Thatte AS (14) Figueroa-Espada CG (15) Ang MJY (16) Murray AM (17) Yamagata HM (18) Kim D (19) Metzloff AE (20) Weissman D (21) Mitchell MJ

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Zeng, Xu, and Wang et al. developed an optimized cancer vaccine platform comprising a novel LNP co-encapsulating tumor antigen mRNA and two STING agonists. In primary BM-DCs, vaccination synergistically boosted CD80/CD86 expression and IFN-I secretion, and in mice, it enhanced antigen cross-presentation in spleens and tdLNs to induce antigen-specific CD8+ cytotoxic and memory T cell expansion. In tumor models, i.v. vaccine delivery inhibited s.c. tumor growth and vascularization. Vaccination upregulated gene sets for apoptosis and antigen processing, and reprogrammed immunosuppressive TAMs to a proinflammatory phenotype.

Contributed by Paula Hochman

ABSTRACT: mRNA-based cancer vaccines offer a modular and safe platform to elicit antitumor immunity, yet their efficacy is often limited by inefficient mRNA delivery and inadequate dendritic cell (DC) activation, both of which are essential for initiating robust cytotoxic T cell responses. Inadequate innate immune activation coupled with poor antigen presentation further diminishes their effectiveness, particularly in immunologically "cold" tumors. While stimulator of interferon genes (STING) agonists can enhance DC maturation and cross-presentation, their therapeutic utility is constrained by poor intracellular delivery and limited colocalization with tumor antigens. In this study, we developed a lipid nanoparticle (LNP) platform via high-throughput screening of ionizable lipids for potent mRNA delivery to DCs both in vitro and in vivo. To amplify immune activation, we coencapsulated the STING agonists c-di-AMP (AMP) and manganese (Mn(2+)) together with tumor antigen-encoding mRNA into the lead LNP formulation. This codelivery strategy synergistically activated type I interferon signaling, upregulated costimulatory molecules, enhanced antigen presentation, and elicited potent tumor-specific T cell responses and superior antitumor efficacy. Our results demonstrate that integrating innate immune stimulation with mRNA-LNP delivery provides a promising strategy to overcome current limitations in mRNA vaccine efficacy and to improve cancer immunotherapy outcomes.

Author Info: (1) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (2) Department of Bioengineering, University of Pennsylvania, P

Author Info: (1) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (2) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (3) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (4) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (5) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (6) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (7) Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing 100190, China. ROR: https://ror.org/04f49ff35 (8) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (9) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (10) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (11) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (12) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (13) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (14) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (15) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Republic of Singapore, Singapore 138668, Singapore. ROR: https://ror.org/036wvzt09 (16) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (17) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (18) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (19) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (20) Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (21) Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 Center for Precision Engineering for Health, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10

Citation: Proc Natl Acad Sci U S A 2026 Jul 14 123:e2525718123 Epub07/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42418483

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RIG-I-targeted immunotherapy synergizes with immune checkpoint inhibition in a hepatocellular carcinoma model Spotlight 

(1) Marx C (2) Teppert J (3) Marisch L (4) Formisano S (5) Senz A (6) Boehmer DFR (7) Metzger P (8) Kechur D (9) Delius L (10) Hoerth C (11) Lauber K (12) Mayr D (13) De Toni EN (14) Helms MW (15) Brunner B (16) Endres S (17) Schnurr M (18) Duewell P (19) Rothenfusser S (20) Koenig LM

Molecular cancer therapeutics

Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

Contributed by Paula Hochman

(1) Marx C (2) Teppert J (3) Marisch L (4) Formisano S (5) Senz A (6) Boehmer DFR (7) Metzger P (8) Kechur D (9) Delius L (10) Hoerth C (11) Lauber K (12) Mayr D (13) De Toni EN (14) Helms MW (15) Brunner B (16) Endres S (17) Schnurr M (18) Duewell P (19) Rothenfusser S (20) Koenig LM

Molecular cancer therapeutics

Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

Contributed by Paula Hochman

ABSTRACT: Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic pattern recognition receptor that senses short double-stranded RNA with uncapped 5'-triphosphate (3p-RNA). Upon activation, RIG-I induces type I interferons and proinflammatory cytokines, thereby promoting adaptive immunity. Thus, RIG-I activation is a promising approach for creating a proinflammatory tumor microenvironment. In this study, we investigated its therapeutic potential in hepatocellular carcinoma (HCC). We explored and confirmed RIG-I expression and signaling in human HCC samples and cell lines. The therapeutic potential of RIG-I activation by 3p-RNA for the treatment of HCC was investigated in vitro and in syngeneic murine orthotopic tumor models. In vivo, 3p-RNA treatment significantly reduced the tumor burden, delayed disease progression, and achieved partial complete remission of RIL-175 tumors with durable immune memory. However, no therapeutic effects were observed in the Hep-55.1C model. Tumor clearance depended on CD4⁺ and CD8⁺ T cells, but not NK cells. Additionally, 3p-RNA induced PD-L1 expression on HCC cells, enhancing their sensitivity to anti-PD-1 immune checkpoint therapy in vivo. RIG-I activation via 3p-RNA therapy shows promise as an immunotherapeutic strategy for hepatocellular carcinoma (HCC). Future investigations need to focus on tumor-intrinsic factors to understand heterogeneity between tumors and to overcome resistance mechanisms.

Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.or

Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (4) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (5) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (6) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (7) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (8) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (9) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (10) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (11) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (12) Ludwig-Maximilians-UniversitŠt MŸnchen Munich, Bavaria Germany. ROR: https://ror.org/05591te55 (13) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (14) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (15) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (16) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (17) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (18) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (19) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (20) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32

Citation: Mol Cancer Ther 2026 Jun 25 Epub06/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42345470

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Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial

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(1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

Nature medicine

De Caluwé et al. conducted a phase 2 clinical trial in patients with ER+HER2- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

(1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

Nature medicine

De Caluwé et al. conducted a phase 2 clinical trial in patients with ER+HER2- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

ABSTRACT: Patients with estrogen receptor-positive (ER+), HER2-negative, early breast cancer (BC) have low pathologic complete response (pCR) rates following neoadjuvant chemotherapy. Immune checkpoint inhibitors (ICIs) provide limited benefit in programmed death-ligand 1 (PD-L1)-negative tumors, characterized by an immune-cold tumor microenvironment. Here we hypothesized that immune-modulating stereotactic body radiation therapy (iSBRT; 3 × 8 Gy) could enhance response through tumor microenvironment reprogramming, and that CD73 blockade could further improve efficacy. We conducted a phase 2, randomized, multicenter trial (Neo-CheckRay) in 147 female patients with high-risk, ER+HER2- early BC. Patients received neoadjuvant chemotherapy plus iSBRT alone (No_ICI), with anti-PD-L1 durvalumab (Single_ICI) or with durvalumab plus anti-CD73 oleclumab (Double_ICI). In the intention-to-treat population, the primary endpoint, residual cancer burden 0/1 rate, was 35.4% with No_ICI, 45.1% with Single_ICI and 47.9% with Double_ICI, without statistically significant differences. pCR rates were 16.7%, 29.4% and 33.3%, respectively (P = 0.059). In the per-protocol population (MammaPrint High Risk, n = 131), pCR rates were 16.3%, 32.6% and 35.6%, respectively (P = 0.040). Among PD-L1-negative tumors (n = 91), pCR rates were 3.4%, 28.1% and 30.0%, respectively. No new safety signals were observed. Baseline transcriptomic analysis showed low immune signature expression in PD-L1-negative tumors. Paired baseline and on-treatment biopsies obtained 1 week after iSBRT demonstrated tumor microenvironment reprogramming toward an inflamed phenotype in the iSBRT + anti-PD-L1 arms. These findings suggest that iSBRT + anti-PD-L1 may convert immune-cold ER+HER2- BC into more inflamed tumors and improve response, particularly in PD-L1-negative disease. ClinicalTrials.gov registration: NCT03875573 .

Author Info: (1) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franoi

Author Info: (1) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franois Leclerc, UniversitŽ Bourgogne Europe, Dijon, France. (3) Institut Curie, Paris, France. (4) CHU St Elisabeth, Namur, Belgium. (5) Universitaire Ziekenhuizen Leuven, Leuven, Belgium. (6) H™pital Universitaire St Luc, Brussels, Belgium. (7) Centre Georges-Franois Leclerc, UniversitŽ Bourgogne Europe, Dijon, France. (8) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (9) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (10) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (11) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (12) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (13) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (14) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (15) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (16) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (17) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (18) ZAS Hospitals, Antwerp, Belgium. Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia. (19) Iridium Netwerk, Antwerp, Belgium. University of Antwerp, Antwerp, Belgium. (20) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. (21) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (22) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (23) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (24) Institut Curie, Paris, France. (25) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium.

Citation: Nat Med 2026 Jun 25 Epub06/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350643

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CDK4/6 inhibition enhances CAR-T cell therapy in solid tumors Spotlight 

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19+ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19+ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

ABSTRACT: CDK4/6 inhibitors promote anti-tumor immunity through diverse mechanisms, positioning them as promising adjuvants to cancer immunotherapies. While CDK4/6 inhibitors have demonstrated strong synergy with immune checkpoint inhibitors across numerous preclinical cancer models, their combination with CAR-T cell therapy remains unexplored. In this study, we examined the efficacy of combined CDK4/6 inhibition (trilaciclib) and CAR-T therapy across a range of preclinical blood and solid cancer models. In vitro, trilaciclib enhanced human CAR-T cell cytotoxicity and metabolic fitness while reducing expansion. In vivo, the combination outperformed single agents against retinoblastoma protein (RB)-proficient, trilaciclib-sensitive CD19+ leukemia. However, in an equivalent RB-deficient model, the combination therapy was no more effective than CAR-T cells alone, suggesting that enhanced CAR-T cell function may be offset by reduced expansion. In contrast, in solid cancer models the combination was consistently more efficacious than either monotherapy. Notably, combination effects were most pronounced in immunocompetent mouse models, including a model with poor sensitivity to trilaciclib as a monotherapy. Mechanistically, CDK4/6 inhibition reduced tumor-infiltrating T-regulatory cells while enhancing CD8+ CAR-T cell persistence, tumor trafficking, and cytotoxic function within the tumor. Together, these findings suggest that trilaciclib and CAR-T cell therapy may be an effective combinatorial treatment for solid cancers.

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VI

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: emily.lelliott@petermac.org. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (3) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (8) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (10) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (13) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (15) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: shom.goel@petermac.org. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: jane.oliaro@petermac.org.

Citation: Mol Ther 2026 Jul 1 34:4021-4034 Epub03/24/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41883164

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A radiopharmaceutical enhances CAR T cells against radio-sensitive and radio-resistant neuroblastoma by tumor sensitization and TME remodeling Spotlight 

(1) Rodriguez C (2) Edinger RS (3) Diehl G (4) Reyes-Gonz‡lez JM (5) Lee W (6) Buckley J (7) Oh J (8) Nambiar D (9) Baidoo K (10) Okada R (11) Phadke I (12) Schmiechen Z (13) Khan H (14) Sakhalkar Y (15) Cortez AG (16) Josefsson A (17) Nedrow JR (18) White A (19) Citrin DE (20) Zhang X (21) Anderson CJ (22) Escorcia FE (23) Patel RB (24) Nguyen R

Cell reports. Medicine

Rodriguez and Edinger et al. showed that pre-treatment with VLA-4-targeted, low-dose radiopharmaceutical therapy (RPT) using [67Cu] Cu-LLP2A enhanced GD2 or B7-H3 CAR T cell efficacy, resulting in significant tumor regression in xenogeneic, preclinical neuroblastoma models. The mechanism of action varied with tumor radiosensitivity. In radiosensitive tumors, RPT was directly tumoricidal and enhanced CAR T cell efficacy via TNF-α, leading to paracrine T cell activation. In radioresistant tumors, RPT remodeled the TIME by decreasing the number of M2-like TAMs and stimulating the formation of enriched cytotoxic CD4+ and CD8+ T cell clusters.

Contributed by Katherine Turner

(1) Rodriguez C (2) Edinger RS (3) Diehl G (4) Reyes-Gonz‡lez JM (5) Lee W (6) Buckley J (7) Oh J (8) Nambiar D (9) Baidoo K (10) Okada R (11) Phadke I (12) Schmiechen Z (13) Khan H (14) Sakhalkar Y (15) Cortez AG (16) Josefsson A (17) Nedrow JR (18) White A (19) Citrin DE (20) Zhang X (21) Anderson CJ (22) Escorcia FE (23) Patel RB (24) Nguyen R

Cell reports. Medicine

Rodriguez and Edinger et al. showed that pre-treatment with VLA-4-targeted, low-dose radiopharmaceutical therapy (RPT) using [67Cu] Cu-LLP2A enhanced GD2 or B7-H3 CAR T cell efficacy, resulting in significant tumor regression in xenogeneic, preclinical neuroblastoma models. The mechanism of action varied with tumor radiosensitivity. In radiosensitive tumors, RPT was directly tumoricidal and enhanced CAR T cell efficacy via TNF-α, leading to paracrine T cell activation. In radioresistant tumors, RPT remodeled the TIME by decreasing the number of M2-like TAMs and stimulating the formation of enriched cytotoxic CD4+ and CD8+ T cell clusters.

Contributed by Katherine Turner

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as neuroblastoma (NB). Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [(67)Cu]Cu-LLP2A and show that it potentiated the anti-tumor activity of CAR T cells in radio-sensitive and radio-resistant NB models via distinct mechanisms. In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T cell efficacy through pro-immune pathways, most notably via the TNF-_ pathway, leading to paracrine activation of T cells. In radio-resistant NB, RPT improves CAR T cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8(+) GZMB(+) and CD4(+) GZMB(+) CAR T cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.

Author Info: (1) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Department of Radiation Oncology, Univer

Author Info: (1) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (3) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (4) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (5) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (6) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (7) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (8) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (9) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (10) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (11) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (12) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (13) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (14) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (15) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (16) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (17) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (18) Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19) Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (20) Rutgers Cancer Institute, New Brunswick, NJ, USA; Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. (21) Departments of Chemistry and Radiology, University of Missouri, Columbia, MO, USA. (22) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: freddy.escorcia@gmail.com. (23) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Biomedical Engineering, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: patelr20@upmc.edu. (24) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: hongharosa.nguyen@nih.gov.

Citation: Cell Rep Med 2026 Jun 23 102884 Epub06/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42335901

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Activation of tumor-specific CD8+ T cells prior to radiopharmaceutical therapy improves antitumor response Spotlight 

(1) Shim D (2) Mouton C (3) Moseman JE (4) Comas Rojas H (5) Jeon D (6) Idrissou MB (7) Hernandez R (8) Weichert JP (9) McNeel DG

Journal for immunotherapy of cancer | Free PMC Article

Shim et al. investigated how the timing of tumor antigen-specific CD8+ T cell activation shaped responses to radiopharmaceutical therapy with ⁹⁰Y-NM600 (RPT) in E.G7-OVA and TRAMP-C1 tumor models. Low-dose RPT led to an increase in CD8+ T cell infiltration, but failed to enrich antigen-specific CD8+ T cells. Ex vivo- or (with vaccination) in vivo-activated, but not naive, OT-I cells given prior to RPT slowed tumor growth and expanded antigen-specific effector memory CD8+ T cells in a type I IFN-dependent, cGAS–STING-independent manner. In the TRAMP-C1 prostate cancer model, an AR-encoding DNA vaccine given prior to RPT enhanced tumor control.

Contributed by Shishir Pant

(1) Shim D (2) Mouton C (3) Moseman JE (4) Comas Rojas H (5) Jeon D (6) Idrissou MB (7) Hernandez R (8) Weichert JP (9) McNeel DG

Journal for immunotherapy of cancer | Free PMC Article

Shim et al. investigated how the timing of tumor antigen-specific CD8+ T cell activation shaped responses to radiopharmaceutical therapy with ⁹⁰Y-NM600 (RPT) in E.G7-OVA and TRAMP-C1 tumor models. Low-dose RPT led to an increase in CD8+ T cell infiltration, but failed to enrich antigen-specific CD8+ T cells. Ex vivo- or (with vaccination) in vivo-activated, but not naive, OT-I cells given prior to RPT slowed tumor growth and expanded antigen-specific effector memory CD8+ T cells in a type I IFN-dependent, cGAS–STING-independent manner. In the TRAMP-C1 prostate cancer model, an AR-encoding DNA vaccine given prior to RPT enhanced tumor control.

Contributed by Shishir Pant

BACKGROUND: Radiopharmaceutical therapy (RPT) delivers radiation systemically, enabling the treatment of metastatic cancers. Beyond killing tumor cells, RPT can modulate the tumor immune microenvironment. With RPTs and immunotherapies already approved or in development for prostate cancer, many preclinical and clinical studies are evaluating their use in combination. However, due to the radiosensitivity of tumor-infiltrating lymphocytes, further studies are needed to determine the effects of RPT on these cells to better inform the sequence of immunotherapies that activate T cells when given with RPT. METHODS: E.G7-OVA tumor-bearing mice received na•ve or activated OT-I CD8+T cells prior to or following the administration of RPT using (90)Y-NM600. Changes in tumor growth were monitored, and tumor-infiltrating lymphocytes were evaluated for phenotypic and functional markers. The murine prostate tumor model TRAMP-C1 was used to evaluate this approach using tumor antigen-specific vaccination with (90)Y-NM600. RESULTS: Antitumor efficacy was improved if OT-I CD8+T cells were present and activated prior to (90)Y-NM600 administration than if the cells were delivered after RPT. Similarly, in vivo activation of adoptively transferred OT-I CD8+T cells, using ovalbumin (OVA)-specific vaccination, prior to RPT slowed tumor growth and increased the frequency of tumor-infiltrating OVA(257-264)-specific CD8+T cells with effector memory phenotype and effector molecule production. Blockade of type I interferon, but not the upstream inhibition of stimulator of interferon genes, abrogated tumor growth delay resulting from the combination treatment. Tumor antigen-specific vaccination prior to (90)Y-NM600 administration similarly improved antitumor outcomes in the TRAMP-C1 tumor model. CONCLUSIONS: Our study suggests that tumor-specific CD8+T cells need to be present and activated prior to RPT to enhance antitumor outcomes. This study highlights the importance of considering the effects of RPT on tumor-infiltrating CD8+T cells when combining other T-cell activating therapies with RPT, as they may similarly display sequence-dependent antitumor outcomes.

Author Info: (1) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (2) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (3) University of Wisconsin

Author Info: (1) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (2) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (3) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (4) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (5) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (6) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (7) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (8) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. (9) University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA dm3@medicine.wisc.edu.

Citation: J Immunother Cancer 2026 Jun 19 14: Epub06/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42320982

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Tumor irradiation promotes antigen dressing of dendritic cells to enhance CAR T cell persistence and efficacy in lung metastases Spotlight 

(1) Navarre S (2) Ishibashi MN (3) Nair A (4) Reyes-Torres I (5) Belabed M (6) Halasz L (7) Park MD (8) Mattiuz R (9) Ounadjela M (10) Gunset G (11) Mansilla-Soto J (12) Feucht J (13) Cabriolu A (14) Le Berichel J (15) Birbrair A (16) Eyquem J (17) Brown BD (18) Merad M (19) Sadelain M (20) Ahmed J

Nature cancer

Navarre, Ishibashi, and Nair et al. showed that focal 8 Gy tumor irradiation in a syngeneic metastatic lung adenocarcinoma model enhanced CAR T cell persistence and efficacy in a DC-dependent manner. Irradiation conditioned tumor cells for trogocytic antigen transfer onto DCs and macrophages, but only DCs engaged CAR T cells through the chimeric receptor, sustaining their activity. DC depletion abolished sustained CAR T cells and long-term tumor control. CAR T cell expansion was restricted to irradiated tumors, and not adjacent antigen-expressing normal lung tissue, indicating spatially restricted DC–CAR T cell engagement.

Contributed by Shishir Pant

(1) Navarre S (2) Ishibashi MN (3) Nair A (4) Reyes-Torres I (5) Belabed M (6) Halasz L (7) Park MD (8) Mattiuz R (9) Ounadjela M (10) Gunset G (11) Mansilla-Soto J (12) Feucht J (13) Cabriolu A (14) Le Berichel J (15) Birbrair A (16) Eyquem J (17) Brown BD (18) Merad M (19) Sadelain M (20) Ahmed J

Nature cancer

Navarre, Ishibashi, and Nair et al. showed that focal 8 Gy tumor irradiation in a syngeneic metastatic lung adenocarcinoma model enhanced CAR T cell persistence and efficacy in a DC-dependent manner. Irradiation conditioned tumor cells for trogocytic antigen transfer onto DCs and macrophages, but only DCs engaged CAR T cells through the chimeric receptor, sustaining their activity. DC depletion abolished sustained CAR T cells and long-term tumor control. CAR T cell expansion was restricted to irradiated tumors, and not adjacent antigen-expressing normal lung tissue, indicating spatially restricted DC–CAR T cell engagement.

Contributed by Shishir Pant

ABSTRACT: Metastatic solid tumors remain the principal cause of cancer mortality worldwide. High tumor burden impairs responses to chimeric antigen receptor (CAR) T cell therapy, yet off-tumor toxicity limits the doses that can be safely delivered. Strategies to selectively enhance CAR T cell activity at tumor sites could widen the therapeutic window. Using syngeneic models of extensive metastatic lung adenocarcinoma and melanoma, we show that 8_Gy of tumor irradiation significantly enhanced CAR T cell persistence in a manner critically dependent on dendritic cells (DCs). Irradiation promoted trogocytic antigen dressing of tumor antigens onto DCs, which then expanded CAR T cells through the chimeric receptor. Without functional DCs, irradiation failed to sustain CAR T cell persistence and tumors relapsed. Irradiation increased CAR T cell numbers within tumors but not in adjacent normal lung tissue that also expressed target antigen, conferring robust control of tumor without increased toxicity. These data define a mechanistic basis and rationale for combining radiotherapy with CAR T cell therapy.

Author Info: (1) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department

Author Info: (1) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Biomedical Engineering, The City College of New York, New York, NY, USA. (2) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (3) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Columbia Initiative in Cell Engineering and Therapy (CICET), Cancer Cell Therapy Initiative in the Vagelos Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (11) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (12) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cluster of Excellence iFIT (EXC2180) 'Image-guided and Functionally Instructed Tumor Therapies', University Children's Hospital TŸbingen, TŸbingen, Germany. (13) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Columbia Initiative in Cell Engineering and Therapy (CICET), Cancer Cell Therapy Initiative in the Vagelos Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (14) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Department of Dermatology, University of Wisconsin-Madison, Madison, WI, USA. (16) Department of Medicine-Division of Hematology and Oncology, Gladstone-UCSF Institute of Genomic Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA, USA. (17) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (18) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (19) Columbia Initiative in Cell Engineering and Therapy (CICET), Cancer Cell Therapy Initiative in the Vagelos Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (20) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jalal.ahmed@mountsinai.org. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jalal.ahmed@mountsinai.org.

Citation: Nat Cancer 2026 May 22 Epub05/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42174275

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Radiotherapy synergizes with an inducible AAV-based immunotherapy platform to program local and systemic antitumor immunity

Spotlight 

Sonia Marco 1; Myriam Fernández 1; Beatriz Honorato 1; Nerea Juanarena 1; Cristina Sainz 1; Ainhoa Andueza 1; David J. Gould 2; Seth Anderson 3; Carlos de Andrea 4,5 Paulo Pérez Domínguez 4,5 Paolo Wong 1; Carlos Vásquez 1; Irene Narinda 1; Carmen Unzu 6; Sergio Isola 6; Beatriz Tavira 1; Mikel Ariz 7; Gracián Camps 4,8; Miguel F. Sanmamed 4,8,9; Julián Pardo 10; Sara Labiano 1,4,11; Marta M. Alonso 1,4,11; Javier Marco-Sanz 1,4,11; Elizabeth Guruceaga 4,12; María Collantes 3,13; Jon Ander Simón 4,13; Iván Peñuelas 4,13; Joaquín Fernández-Irigoyen 14; Enrique Santamaría 14; Jesús Prieto 1,15; Juan Dubrot 1,15,16.

Cancer Cell

Marco et al. sought to expand the utility of immunizing radiation (IR) therapy by intratumorally delivering agents to remodel the tumor immune microenvironment (TIME). After observing that IR enhanced transduction of tumor cells by adeno-associated viruses (AAVs), a known durable and safe gene delivery system, AAVs were engineered to express IL-12 under the control of a type I interferon promoter (as IFN-I is highly induced in tumors by IR). Tumor irradiation followed rapidly by AAV injection led to enhanced local IL-12 expression, remodeled the TIME, and induced robust synergistic tumor elimination in multiple models, primarily through FAS-FASL cytotoxicity.

Contributed by Ed Fritsch

Sonia Marco 1; Myriam Fernández 1; Beatriz Honorato 1; Nerea Juanarena 1; Cristina Sainz 1; Ainhoa Andueza 1; David J. Gould 2; Seth Anderson 3; Carlos de Andrea 4,5 Paulo Pérez Domínguez 4,5 Paolo Wong 1; Carlos Vásquez 1; Irene Narinda 1; Carmen Unzu 6; Sergio Isola 6; Beatriz Tavira 1; Mikel Ariz 7; Gracián Camps 4,8; Miguel F. Sanmamed 4,8,9; Julián Pardo 10; Sara Labiano 1,4,11; Marta M. Alonso 1,4,11; Javier Marco-Sanz 1,4,11; Elizabeth Guruceaga 4,12; María Collantes 3,13; Jon Ander Simón 4,13; Iván Peñuelas 4,13; Joaquín Fernández-Irigoyen 14; Enrique Santamaría 14; Jesús Prieto 1,15; Juan Dubrot 1,15,16.

Cancer Cell

Marco et al. sought to expand the utility of immunizing radiation (IR) therapy by intratumorally delivering agents to remodel the tumor immune microenvironment (TIME). After observing that IR enhanced transduction of tumor cells by adeno-associated viruses (AAVs), a known durable and safe gene delivery system, AAVs were engineered to express IL-12 under the control of a type I interferon promoter (as IFN-I is highly induced in tumors by IR). Tumor irradiation followed rapidly by AAV injection led to enhanced local IL-12 expression, remodeled the TIME, and induced robust synergistic tumor elimination in multiple models, primarily through FAS-FASL cytotoxicity.

Contributed by Ed Fritsch

ABSTRACT: Radiotherapy (RT) can prime the immune system against cancer but often fails to generate effective antitumor responses due to concomitant induction of immunosuppressive factors. To overcome this limitation, we built upon the observation that RT enhances adeno-associated vectors (AAVs) tumor transduction through the epigenetic modification of vector episomes. We designed an AAV-based platform to deliver immunostimulatory cytokines through an interferon (IFN)-inducible promoter that allows for spatial control of transgene expression into irradiated tumors. As opposed to a constitutive system, local delivery of a vector encoding for inducible IL-12 (AAV-iIL12) achieves an efficient production of the cytokine without significant toxicity. Combination of RT and AAV-iIL12 generates a highly immunostimulatory tumor microenvironment (TME) leading to robust local and systemic antitumor responses in an IFNγ- and FAS-dependent manner, able to overcome common immune-evasion mechanisms. Our work shows that radiation coupled with AAV-based immune-gene delivery is an efficient and safe approach to treat cancer.

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Citation: Epub

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