bims-tuinly 2026-07-12 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–07–12
28 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

AI-Based Analysis of Tumor-Infiltrating Lymphocytes and Homologous Recombination in Ovarian Cancer: JGOG3025-A1 Study.
Association between cumulative lifetime exposure to reproductive hormones and tumor-infiltrating lymphocytes, CD4 +, and CD8 + T cells among women with breast cancer.
Preclinical proof of concept for a personalized SNAP™-TIL (Specific Neo-Antigen Peptides-TIL) therapy platform.
Association of tumor-infiltrating lymphocytes and proinflammatory biomarkers with breast cancer molecular subtypes: analysis of the MEND study.
Revealing the dynamics of follicular T cells and checkpoint engagement in surgically resected colorectal cancer and their relations to clinicopathological aspects.
Letter to the Editor for submission to journal of translational medicine contextual programming of CAR‑enhanced TIL.
The MHCII Immune Activation Score predicts risk of recurrence and benefit of taxanes in Basal-like and HER2-enriched breast cancer.
Engineering T cell metabolism to enhance therapeutic efficacy.
TLR9 Agonists Potentiate Adoptive T Cell Therapy in Cancer through a B Cell-CD2 Costimulatory Axis.
Tumor-driven stabilization of CD8+ T cell exhaustion and implications for cancer immunotherapy.
HER2-directed TAC T cells in solid tumors: a step forward, but not yet a therapeutic leap.
De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.
Adenosine as a metabolic checkpoint in CD8+ T cell dysfunction.
Molecular effects of ovarian stimulation for fertility preservation in breast cancer: a paired-biopsy analysis.
CD137 in cancer therapy - bench to bedside.
Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells.
Integrin-mediated mechanotransduction in the tumor microenvironment: macrophage-centered signaling mechanisms and immune remodeling.
Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses.
PD-1⁺ CD8⁺ T cells: roles of PD-1 beyond an exhaustion marker.
Tumor Microenvironment: The Kingpin in the Emergence of Resistance to Cancer Therapy.
T Cell subsets for therapy-unconventional CD1d-restricted natural killer T cells.
B cell-intrinsic IRF8 transcriptionally reprograms antigen presentation to sustain CD8⁺ T cell antitumor immunity.
A deep learning model to predict objective response to TACE and TKI-based therapy in HBV-related uHCC.
Tissue-resident CD8+ T cells link pregnancy to breast cancer protection.
Metabolically and epigenetically reprogrammed splenic TRNP1hiCD8+ T cells exacerbate liver fibrosis.
Beyond the Count: Critical Gaps in Intraepithelial Lymphocyte-Based Progression Markers of Potential Autoimmune Gastritis.
Suppression of the myofibroblastic cancer-associated fibroblast phenotype to enhance anti-PD-1 response.
Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation.

Cancer Sci. 2026 Jul 10.

AI-Based Analysis of Tumor-Infiltrating Lymphocytes and Homologous Recombination in Ovarian Cancer: JGOG3025-A1 Study.

Kohei Hamada, Junzo Hamanishi, Noriomi Matsumura, Akihiko Ueda, Shiro Takamatsu, Kosuke Yoshihara, Takayuki Nagasawa, Toshiyuki Seki, Akira Kikuchi, Etsuko Fujimoto, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Hisaaki Kudo, Katsutoshi Oda, Muneaki Shimada, Aikou Okamoto, Masaki Mandai.

  Understanding the tumor immune microenvironment, especially tumor-infiltrating lymphocytes (TILs), remains crucial in ovarian cancer. However, the distribution and prognostic significance of TILs across histological subtypes and genetic backgrounds remain unclear. As part of the JGOG3025-A1 study, diagnostic slides from 400 cases were collected. Two artificial intelligence-based cell classification models were used to evaluate the spatial distribution of TILs. The TIL score was calculated as the number of TILs divided by the analyzed area, and the immune-inflamed group was defined based on TIL scores. Among histological subtypes, high-grade serous carcinoma (HGSC) exhibited the highest TIL scores, clear cell carcinoma the lowest, and endometrioid carcinoma intermediate values. In HGSC, TIL scores did not significantly differ according to BRCA alteration or homologous recombination deficiency (HRD) status. The HRD/immune-inflamed group had the most favorable prognosis. In the homologous recombination-proficient population, the immune-inflamed group had better progression-free survival, whereas this trend did not appear for overall survival. In analyzes of the relationships between TIL levels and genomic structure, whole-genome doubling was associated with lower TIL infiltration in HRD tumors but showed no association in HRP tumors. In conclusion, HGSC showed the highest amount of TIL infiltration among subtypes, and prognostic stratification can be achieved by integrating pathology-based immunophenotypes and HRD status.

Keywords:  artificial intelligence; deep learning; digital pathology; ovarian cancer; tumor‐infiltrating lymphocytes

DOI:  https://doi.org/10.1111/cas.70474
Cancer Immunol Immunother. 2026 Jul 10.

Association between cumulative lifetime exposure to reproductive hormones and tumor-infiltrating lymphocytes, CD4 +, and CD8 + T cells among women with breast cancer.

Yidan Zhang, Rand T Akasheh, Angela R Omilian, Bo Qin, Nur Zeinomar, Song Yao, Chi-Chen Hong, Elisa V Bandera, Christine B Ambrosone, Thaer Khoury, Ting-Yuan David Cheng.

   BACKGROUND: Reproductive hormones may influence immune responses to tumors. Tumor-infiltrating lymphocytes (TILs), CD4 +, and CD8 + T cell densities are markers of immune activity and breast cancer prognosis. We examined associations between lifetime reproductive hormone exposure, tumor immune infiltration, and survival among women with breast cancer.
METHODS: The study included invasive breast cancer cases in the Women's Circle of Health Study and the Women's Circle of Health Follow-up Study. Lifetime endogenous hormone exposure (LHEendo) was defined as reproductive years plus pregnancy duration minus breastfeeding duration; lifetime exogenous hormone exposure (LHEexo) was defined as the combined cumulative duration of oral contraceptive and hormone replacement therapy use. TILs were scored as ordered percentage values from 0 to 100% stromal area; CD4 + /CD8 + T cell densities were quantified by immunohistochemistry. TILs were modeled using ordinal logistic regression, and CD4 + /CD8 + T cell densities were modeled using gamma generalized linear models among participants with positive density values, with covariates selected by directed acyclic graphs. Overall survival was assessed using Cox proportional hazards models, and breast cancer-specific survival was assessed using Fine-Gray competing-risk models.
RESULTS: Among 1195 women with valid TILs measurements, 553 and 610 had CD4 + and CD8 + T cell density data, respectively. Across all tumor molecular subtypes, a 1-year increment of LHEendo was associated with a 2.85% decrease in CD8 + T cell density (95% CI - 5.14%, - 0.61%). LHEendo was associated with lower odds of being in a higher TIL level among women with hormone receptor (HR) + /HER2- tumors (OR = 0.977, 95% CI 0.957, 0.997), although the interaction by molecular subtype was not statistically significant. LHEexo was associated with lower risk of all-cause mortality (HR = 0.979, 95% CI 0.960, 0.998). TIL-stratified analyses suggested that this association may be more apparent among women with TILs ≥ 50% (HR = 0.90, 95% CI = 0.82, 0.99; P-interaction = 0.10).
CONCLUSIONS: Lifetime endogenous hormone exposure was associated with lower CD8 + T cell density overall, with exploratory findings of lower TIL levels among women with HR + /HER2- tumors. Lifetime exogenous hormone exposure was associated with a lower risk of all-cause mortality, with possible variation by TIL levels.

Keywords:  Breast cancer; CD4-positive T-lymphocytes; CD8-positive T-lymphocytes; Hormone use; Reproductive history; Tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1007/s00262-026-04471-3
Oncoimmunology. 2026 Dec 31. 15(1): 2684383

Preclinical proof of concept for a personalized SNAP™-TIL (Specific Neo-Antigen Peptides-TIL) therapy platform.

Tithi Ghosh Halder, Erin Kelley, Jorge Soria-Bustos, Trason Thode, Serina Ng, Taylor Bargenquast, Alexis Weston, Ryan Rodriguez Del Villar, Mohan Kaadige, Erkut Borazanci, Michael Gordon, Justin Moser, Frank Tsai, Saul J Priceman, Stephen J Forman, Yan Xing, John A Altin, Raffaella Soldi, Sunil Sharma.

  Tumor-infiltrating lymphocyte (TIL) therapy, which involves extracting, expanding, and reinfusing immune cells to target cancer cells, has shown promise in melanoma treatment, but requires optimization for broader efficacy. The success of TIL therapy depends on the recognition of tumor-associated antigens, but neoantigen-reactive T-cells are often rare and exhausted in less immunogenic malignancies. Isolating T cells enriched in neoantigen reactivity prior to in vitro expansion and reinfusion may improve the response rates. To this end, our proprietary Specific Neo-Antigen Peptides (SNAP™) technology platform improves the accuracy of neoantigen prediction and validation by combining advanced computational modelling and PepSeq, a high-throughput screen for the physical credentialing of putative neoantigens based on their affinity to bind patient-specific HLA class II proteins. This approach allows for the education and enrichment of TILs (SNAP-TILs) with personalized, predefined, highly immunogenic neoantigens prior to expansion. Using the SNAP platform, we consistently achieved, on average, a SNAP-TIL product comprising 96% CD3+ cells, with a mixture of 75% effector and 23% central memory cells. SNAP-TILs exhibited greater efficacy and selectivity in immune infiltration than TIL, which was expanded by the rapid expansion protocol alone using ex vivo models. SNAP-TIL was also reactive in highly and poorly immunogenic tumors, with 70% and 50% tumor growth inhibition in melanoma and pancreatic patient-derived xenograft models, respectively. This study demonstrates the novel benefit of our Personalized Neoantigen Pipeline approach, potentially providing a durable antitumor immune response for a larger proportion of cancer patients.

Keywords:  Adoptive cell therapy; PepSeq; SNAP-TIL; immunotherapy; neoantigens; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1080/2162402X.2026.2684383
Breast Cancer Res Treat. 2026 Jul 10. pii: 10. [Epub ahead of print]218(1):

Association of tumor-infiltrating lymphocytes and proinflammatory biomarkers with breast cancer molecular subtypes: analysis of the MEND study.

Jovita Byemerwa, Drew Neish, Lukeman Forgah, April Deveaux, Oyomoare Osazuwa-Peters, Ashwini Joshi, Omolola Salako, Adetola Daramola, Olusegun Alatise, Gabriel Ogun, Allison Hall, Adewale Adeniyi, Omobolaji Ayandipo, Thomas Olajide, Olalekan Olasehinde, Olukayode Arowolo, Adewale Adisa, Oludolapo Afuwape, Aralola Olusanya, Aderemi Adegoke, Trygve O Tollefsbol, Donna Arnett, Michael J Muehlbauer, Tomi Akinyemiju.

   PURPOSE: Tumor-infiltrating lymphocytes (TILs) and proinflammatory biomarkers shape breast cancer (BC) progression and outcomes. We estimated the association between TILs and BC subtypes in Nigerian women and, in exploratory analyses, evaluated relationships between serum biomarkers (IL-6, IL-8, IL-1β, TNF-α, and leptin), TILs and BC subtypes.
METHODS: TILs were quantified on H&E-stained tumors from 436 treatment-naïve Nigerian BC patients, serum biomarkers (n = 109) were profiled by Meso Scale Discovery immunoassays. TILs and proinflammatory biomarkers were assessed across BC subtypes using descriptive analyses and multinomial logistic regression; cytokine ratios were also explored to characterize TNF-α dominance.
RESULTS: Median age was 49, and subtypes were triple-negative (TNBC, 43%), luminal A (31%), luminal B (12%), and HER2-enriched (15%). Median TIL percentage was 10.0 (Q1, Q3: 4.0, 21.0), with 49% of patients classified as low TIL (< 10%), 41% as intermediate (10- < 40%) and 10% as high (≥ 40%). Compared to low TILs, medium (OR 1.94, 95% CI 1.11-3.38, p = 0.020) and high TILs (OR 2.65, 95% CI 1.00-6.99, p = 0.049) were associated with higher odds of TNBC vs. ER+ after demographic and clinical adjustments. TNF-α correlated with TILs (ρ: 0.21; p = 0.026) and higher TNF-α:IL-1β (OR 4.16, 95% CI 1.35-12.84) and TNF-α:IL-8 (OR 3.81, 95% CI 1.29-11.23) ratios were associated with TNBC but not HER2 (vs. ER+); individual biomarkers were not associated with subtypes.
CONCLUSION: Elevated TILs and TNF-α-dominant profiles are associated with TNBC (vs. ER+) in Nigerian women, highlighting potential immunotherapy relevance in Nigerian TNBC cases and a suggestive prognostic/therapeutic role for TNF-α.

Keywords:  Breast cancer; Proinflammatory biomarkers; TNF-α; Triple negative breast cancer; Tumor-associated lymphocytes

DOI:  https://doi.org/10.1007/s10549-026-08022-3
Clin Transl Oncol. 2026 Jul 08.

Revealing the dynamics of follicular T cells and checkpoint engagement in surgically resected colorectal cancer and their relations to clinicopathological aspects.

Asmaa M Zahran, Nahla M Elsherbiny, Alshimaa G Abdelhakeem, Amal Rayan, Zainab Gaber Mahran, Ahmed Khalid Ibrahim Elsayh, Emad Saad, Ahmed Refaat, Radwan Abdelsabour, Doaa A Gamal, Wageeh A Ali, Zeinab Albadry M Zahran, Hossam Elashmawy, Shimaa Gafar Mansor.

   BACKGROUND: Follicular T cells contribute to B-cell responses and antitumor immunity, yet their immune checkpoint expression and role in colorectal cancer (CRC) remain insufficiently characterized. We evaluated the distribution, activation status, and checkpoint expression of follicular helper and follicular cytotoxic T-cell subsets (Tfh and Tfc) in CRC patients and their association with clinicopathological features.
METHODS: Thirty-three CRC patients and 25 healthy controls were recruited from South Egypt Cancer Institute, Assiut University. Flow cytometry was used to assess follicular T-cell subsets and their expression of inducible T-cell costimulatory (ICOS), T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and V-domain Ig Suppressor of T-cell Activation (VISTA).
RESULTS: Tfh and Tfc cells were significantly increased in peripheral blood of CRC patients compared with controls (p < 0.001 and p = 0.006, respectively). Their frequencies were higher in tumor-infiltrating lymphocytes (TILs) than in normal colonic tissue (p = 0.002 and p < 0.001) and peripheral blood (p < 0.001). Their ICOS expression was significantly elevated in patients' blood (p = 0.008 and p = 0.04) and highest in TIL (p = 0.02) compared to the normal tissue and peripheral blood of patients (p < 0.001). TIGIT⁺VISTA⁺ follicular T-cell subsets were significantly expanded in the peripheral blood of patients, with peak expression in TILs (p < 0.001).
CONCLUSIONS: Follicular T cells are enriched and highly activated in CRC, particularly within the tumor microenvironment. The predominance of TIGIT+ VISTA+ subsets suggests a dual role in antitumor immunity and immune escape. These cells serve as biomarkers and potential targets for immunotherapy.

Keywords:  Colorectal cancer; ICOS; Immune checkpoints; T follicular cells; TIGIT; VISTA

DOI:  https://doi.org/10.1007/s12094-026-04468-5
J Transl Med. 2026 Jul 06. pii: 855. [Epub ahead of print]24(1):

Letter to the Editor for submission to journal of translational medicine contextual programming of CAR‑enhanced TIL.

Joana Rapaz Lérias, Jéssica Kamiki, Rodrigo Eduardo, Vitaly Balan, Markus Joseph Maeurer.



Keywords:  CAR-T-cells; Her2; TIL; Transgenic T-cells; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s12967-026-08525-z
medRxiv. 2026 Jul 01. pii: 2026.06.24.26356102. [Epub ahead of print]

The MHCII Immune Activation Score predicts risk of recurrence and benefit of taxanes in Basal-like and HER2-enriched breast cancer.

Philip S Bernard, Bingshu E Chen, Dongxia Gao, Lois E Shepherd, Torsten O Nielsen, Katherine E Varley.

Purpose: There are no clinically validated biomarkers to assess recurrence risk and guide treatment de-escalation in Basal-like and HER2-enriched breast cancer. Taxane-based chemotherapy remains a cornerstone of treatment despite significant toxicity. We evaluated the prognostic and predictive utility of the MHCII Immune Activation Score (IA Score) in these subtypes.
Experimental Design: We retrospectively analyzed Basal-like and HER2-enriched breast cancers from the NCIC CTG MA.21 trial, which randomized patients with node-positive or high-risk node-negative disease to adjuvant chemotherapy with or without taxanes. MA.21 predated immune checkpoint inhibitors and routine HER2-targeted therapy. Subtype was previously assigned by PAM50. The 36-gene MHCII-IA assay used RNA from formalin-fixed, paraffin-embedded tissue. Multivariable Cox and Kaplan-Meier analyses evaluated associations between IA Score, clinicopathologic variables, tumor-infiltrating lymphocytes (TILs), relapse-free survival (RFS), and taxane benefit.
Results: Among Basal-like (N=317) and HER2-enriched (N=155) tumors, higher IA Score was associated with improved RFS independent of lymph node status and provided stronger prognostic discrimination than TILs. Node-negative patients with high IA Score had excellent outcomes (8-year RFS >90%) versus those with low IA Score (8-year RFS <76%). In node-positive disease, high IA Score increased 8-year RFS by >10% relative to low IA Score. IA Score stratified taxane benefit: node-positive IA-low patients benefited, whereas IA-high tumors had favorable outcomes regardless of regimen.
Conclusions: MHCII Immune Activation Score is a prognostic and predictive biomarker in Basal-like and HER2-enriched breast cancer. High IA Score identified patients with excellent outcomes before pembrolizumab, trastuzumab, and taxane-based treatment escalation, providing a rationale for prospective risk-adapted de-escalation strategies.

DOI: https://doi.org/10.64898/2026.06.24.26356102
Adv Pharmacol. 2026 ;pii: S1054-3589(26)00030-X. [Epub ahead of print]106 117-139

Engineering T cell metabolism to enhance therapeutic efficacy.

Laura Anderson, Nicola J Mason, Roddy S O'Connor.

  Adoptive cell therapies, particularly chimeric antigen receptor (CAR) T cells, function as "living drugs" whose efficacy depends not only on target recognition but also on the metabolic state of the infused product. T cell metabolism governs energy production, redox homeostasis, biomass generation, and adaptation to persistent antigen exposure and nutrient stress, thereby shaping expansion, effector function, persistence, and susceptibility to exhaustion. Core metabolic programs relevant to these outcomes include glycolysis and mitochondrial respiration, anaplerosis and amino acid metabolism, lipid metabolism, and NAD- and redox-linked pathways. These programs help determine adoptive cell therapy-relevant phenotypes, including the balance between immediate cytotoxicity and long-term durability. Increasing evidence further suggests that metabolism can be therapeutically manipulated across the lifecycle of adoptive cell therapy through ex vivo manufacturing, receptor and signaling design, direct gene engineering, and post-infusion support. Collectively, these findings support a pharmacologic framework in which metabolic state is not merely a descriptive correlate of product quality, but a controllable determinant of therapeutic performance. A deeper mechanistic understanding of these pathways may enable more precise strategies to improve persistence, function, and long-term antitumor efficacy.

Keywords:  Adoptive cell therapy; CAR T cells; Ex vivo manufacturing; Metabolic engineering; Metabolic programming; Mitochondrial fitness; T cell exhaustion; T cell metabolism; T cell persistence; Tumor microenvironment

DOI:  https://doi.org/10.1016/bs.apha.2026.05.001
Cancer Res. 2026 Jul 06.

TLR9 Agonists Potentiate Adoptive T Cell Therapy in Cancer through a B Cell-CD2 Costimulatory Axis.

Ayana T Ruffin, Vasili Toliopoulos, Aubrey S Smith, Soundharya Kumaresan, Megan M Wyatt, Meredith Salzinger, Anna C Cole, Megen C Wittling, Rachel L Mason, James H Carmouche, Mahmoud A Adelbary, Yuan Liu, Avery D Posey, Gregory B Lesinski, Chrystal M Paulos.

Adoptive T cell transfer (ACT) therapy offers curative potential for some patients with cancer. Toll-like receptor (TLR) agonists improve the efficacy of ACT therapy, and elucidating the underlying mechanism of potency could help determine the best way to maximize the benefits of TLR agonists. Here, we identified an innate-adaptive circuit in which TLR9-activated B cells augment CD8+ T cell fitness and antitumor activity through CD2-dependent costimulation. Among multiple TLR agonists tested, class B CpG uniquely programmed murine and human CD8⁺ T cells for superior effector differentiation, metabolic fitness, and antitumor control. Disruption of CD2 signaling blunted the benefits of TLR9 agonism, including impaired glycolytic capacity and reduced tumor control. Independently, blocking other costimulatory molecules, such as CD86, CD80, CD28 or ICOS, did not impair the antitumor activity of CpG-conditioned T cells. Gain of function experiments revealed that CD2 stimulation recapitulated the effect of TLR9 agonism, bolstering the effector function of tumor infiltrating lymphocytes and CAR T cells. Consistent with these findings, elevated CD2 expression in human tumors correlated with improved overall survival across multiple cancer patient cohorts, underscoring the clinical importance of this signaling cue. Together, these data uncover a non-canonical B cell-CD2 costimulation axis through which TLR9 agonists potentiate ACT, revealing a targetable pathway to overcome resistance to cell therapy in solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0202
Front Immunol. 2026 ;17 1862431

Tumor-driven stabilization of CD8+ T cell exhaustion and implications for cancer immunotherapy.

Romane Thouenon, Marco Ongaro, Grégory Verdeil.

  CD8+ T cell exhaustion is a conserved differentiation program induced by persistent antigen stimulation and originally characterized in chronic infection. In cancer, this program is actively reinforced and stabilized by the tumor microenvironment. Here, we examine how tumors convert a physiological adaptation to chronic stimulation into a deeply entrenched dysfunctional state. Sustained TCR signaling initiates exhaustion through NFAT- and TOX-dependent transcriptional remodeling, but tumor-specific extrinsic pressures, including hypoxia, metabolic competition, ionic imbalance, mechanical stress, and heterogeneous antigen exposure, amplify and stabilize this program. These environmental cues converge on transcription factor networks such as IRF, BATF, NR4A, and NFAT5, which integrate chronic signaling with stress-adaptive responses and progressively restrict effector potential. Exhaustion in tumors becomes epigenetically imprinted. Exhaustion-specific enhancer landscapes persist despite PD-1 blockade, reflecting a lineage-like state enforced by chromatin remodeling factors such as TOX. Thus, checkpoint inhibition transiently restores function without fully reprogramming cellular identity. We propose that tumor-induced exhaustion arises from the layered convergence of chronic antigen signaling and microenvironmental reinforcement, culminating in chromatin fixation. Understanding this stabilization process reframes therapeutic strategies: effective cancer immunotherapy will likely require combinatorial approaches that target not only inhibitory receptors but also metabolic resilience, stress-sensing pathways, and epigenetic architecture. By dissecting how tumors convert adaptive restraint into durable dysfunction, new avenues may emerge to destabilize exhaustion and restore durable antitumor immunity.

Keywords:  T cell exhaustion; cancer; immunotherapies; transcriptional imprinting; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1862431
Ann Oncol. 2026 Jul 07. pii: S0923-7534(26)00995-6. [Epub ahead of print]

HER2-directed TAC T cells in solid tumors: a step forward, but not yet a therapeutic leap.

M Pedregal, V Moreno.

DOI: https://doi.org/10.1016/j.annonc.2026.06.018
Adv Sci (Weinh). 2026 Jul 07. e76202

De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.

Haitao Wang, Tianzhen Hua, Meiling Wang, Bingbing Meng, Yue Zhang, Chengxu Jiang, Yunhe Gao, Hongqi Yang, Jian Bo.

  Cancer-associated cachexia is a devastating syndrome characterized by progressive weight loss, reduced survival, and impaired responses to anticancer therapies. Growth differentiation factor 15 (GDF15), acting through its receptor GFRAL, has emerged as a key mediator of cachexia, yet effective and mechanistically defined strategies to neutralize this pathway remain limited. Here, we applied structure-guided de novo protein design to generate compact minibinders that selectively target the GDF15-GFRAL interaction interface. Using an integrated computational pipeline combining RFdiffusion, ProteinMPNN, and AlphaFold 3 structure prediction, we designed and experimentally validated high-affinity GDF15 minibinders with picomolar-range binding affinities and exceptional structural stability. Mutagenesis and charge-complementary rescue experiments confirm that these minibinders neutralize GDF15 through precisely engineered interface contacts. Functionally, the minibinders suppress GDF15-GFRAL signaling, inhibit downstream transcriptional responses, and robustly reverse cachexia in vivo across multiple tumor models, resulting in significant improvements in body weight and survival. Importantly, neutralization of GDF15 also restores sensitivity to anti-PD-1 immunotherapy in a GDF15-driven resistant tumor model. Combination treatment enhances CD8+ T cell infiltration and effector function within tumors, and its antitumor efficacy is strictly dependent on CD8+ T cells. Together, these findings demonstrate that de novo designed GDF15 minibinders can achieve potent, mechanism-defined neutralization of the GDF15-GFRAL axis in vivo, translating into robust physiological benefits and restoration of immunotherapy efficacy.

Keywords:  GDF15; RFdiffusion; cancer cachexia; de novo protein design; immune checkpoint blockade

DOI:  https://doi.org/10.1002/advs.76202
Trends Immunol. 2026 Jul 08. pii: S1471-4906(26)00161-4. [Epub ahead of print]

Adenosine as a metabolic checkpoint in CD8+ T cell dysfunction.

Arden O Edgerton, Mauricio J Reginato, Michele A Kutzler, Eilas K Haddad.

  CD8+ T cell dysfunction, characterized by impaired effector function, proliferative capacity, and sustained inhibitory receptor expression, limits immune control in both cancer and chronic viral infections. Despite arising from distinct disease processes, these conditions induce a shared state of CD8+ T cell dysfunction, suggesting convergence on common regulatory pathways. Adenosine (ADO), an immunosuppressive purine metabolite generated through extracellular ATP catabolism, has emerged as a context-integrating metabolic checkpoint that regulates immune responses in response to tissue stress and inflammation. Across tumors and HIV, dysregulated ADO signaling reinforces checkpoint pathways and stabilizes dysfunctional CD8+ T cell states. In this review, we examine how the ADO-adenosine deaminase-1 axis shapes CD8+ T cell dysfunction across disease contexts and discuss its potential as a broadly applicable target for immune restoration.

Keywords:  ADA-1; CD8+ T cells; T cell dysfunction; adenosine; chronic infection; tumor microenvironment

DOI:  https://doi.org/10.1016/j.it.2026.06.005
ESMO Open. 2026 Jul 07. pii: S2059-7029(26)02223-4. [Epub ahead of print]11(7): 108281

Molecular effects of ovarian stimulation for fertility preservation in breast cancer: a paired-biopsy analysis.

Y Barral El Gaoui, F Brasó-Maristany, A Borrás Capó, G Casals, I Agustí, G Altinier, N Chic Ruche, P Galván, S Ganau, B González-Farre, C Salvador, S Peon, M Méndez, M Vidal, A Prat, D Manau Trullás.

   BACKGROUND: Fertility preservation is increasingly offered to young women diagnosed with breast cancer. Although available clinical evidence suggests that controlled ovarian stimulation (COS) does not compromise oncological outcomes, its direct biological effect on tumor tissue remains poorly defined.
PATIENTS AND METHODS: In this single-center, longitudinal, prospective paired-biopsy study, 21 premenopausal women (age <40 years) with stage II-III breast cancer underwent paired diagnostic and post-COS tumor biopsies at the Breast Cancer Unit, Clínic BCCC (October 2020-September 2024). COS was carried out with recombinant follicle-stimulating hormone plus concurrent letrozole (5 mg/day) using a random-start protocol. After oocyte retrieval, a second core tumor biopsy was obtained within 24 to 48 hours. Immunohistochemistry [estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (HER2,) tumor-infiltrating lymphocytes (TILs)] and PAM50 gene-expression profiling were carried out. Paired analyses evaluated changes in protein markers, gene-by-gene expression, intrinsic subtype, and risk of recurrence (ROR) score, applying a false discovery rate (FDR) <5% for significance.
RESULTS: No significant differences were detected in ER (P = 0.962), PR (P = 0.562), Ki-67 (P = 0.768), or TILs (P = 0.172) after COS. Post-stimulation Ki-67 was not associated with stimulation duration (r = 0.047; P = 0.839), total gonadotropin dose (r = 0.026; P = 0.911), or peak estradiol levels (r = 0.121; P = 0.610). Transcriptomic analysis identified downregulation of 11/72 genes (15.3%), including proliferation-associated genes CDC6, CENPF, EXO1, and RRM2, although none met significance thresholds after FDR correction. PAM50 intrinsic subtype remained stable (luminal A 23.8%, luminal B 28.6%, HER2-enriched 19.0%, basal-like 23.8%), with only two borderline shifts between luminal A and luminal B. Five mild ROR variations were observed (four decreases and one increase), all small in magnitude on the continuous scale.
CONCLUSIONS: COS with concurrent letrozole was not associated with short-term molecular changes in breast tumor tissue. These findings provide biological reassurance regarding the safety of COS for fertility preservation in young women with breast cancer.

Keywords:  breast cancer; fertility preservation; gene expression; hormone-dependent tumors; ovarian stimulation

DOI:  https://doi.org/10.1016/j.esmoop.2026.108281
Immunotherapy. 2026 Jul 09. 1-17

CD137 in cancer therapy - bench to bedside.

Kathrine S Rallis, Jessica J Liegel, Alexandra Pommier, M Felicia Ciuculescu, José A Cancelas, John G Gribben, David E Avigan.

  CD137 (4-1BB; TNFRSF9) is an inducible costimulatory receptor of the tumor necrosis factor receptor (TNFR) superfamily expressed on activated CD8+ and CD4+ T-cells, natural killer cells, and dendritic cells. By reinforcing T-cell survival, expansion, and memory formation, CD137 has become an attractive target in cancer immunotherapy. Therapeutic strategies include agonistic monoclonal antibodies, bispecific molecules, and adoptive cell therapies enriched for tumor-reactive lymphocytes. Clinical-grade closed bioreactor systems feature a CD137-based enrichment platform utilizing antigen-induced CD137 upregulation to isolate and expand clinically relevant T-cell subsets. Additional innovations such as dendritic cell co-culture systems expressing CD137L and single-cell technologies that characterize highly reactive CD137+ T-cells further enhance precision and potency. Clinical trials of CD137 agonists have shown promising anti-tumor activity; however, hepatotoxicity and variable patient responses remain challenges. Recent work in non-human primate models has clarified the role of CD137 signaling in modulating alloreactivity, with implications for graft-versus-host disease. Despite ongoing barriers - including toxicity, therapeutic resistance, and limited biomarkers - CD137 remains a compelling immunologic target. Future efforts will emphasize context-specific agonism, refined cellular engineering, and multi-omic integration to improve patient selection and therapeutic design. This review summarizes CD137 biology, emerging therapeutic strategies, and translational and clinical directions.

Keywords:  CD137; bispecifics; cancer; immunotherapy; monoclonal antibodies

DOI:  https://doi.org/10.1080/1750743X.2026.2700925
Mol Ther. 2026 Jul 04. pii: S1525-0016(26)00563-0. [Epub ahead of print]

Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells.

Lynsey M Whilding, Ana C Parente-Pereira, Tomasz Zabinski, David M Davies, Roseanna M G Petrovic, Y Vincent Kao, Shobhit A Saxena, Alex Romain, Jose A Costa-Guerra, Shelia Violette, Hiroaki Itamochi, Sadaf Ghaem-Maghami, Sabari Vallath, John F Marshall, John Maher.

DOI: https://doi.org/10.1016/j.ymthe.2026.06.039
J Transl Med. 2026 Jul 08.

Integrin-mediated mechanotransduction in the tumor microenvironment: macrophage-centered signaling mechanisms and immune remodeling.

Guanghui Liu, Qi Sun, Yuting Zhong, Lijuan Liu, Changgang Sun.

   BACKGROUND: Tumor-associated macrophages (TAMs) play a critical role in the immunosuppressive tumor microenvironment (TME). Although the biochemical signaling pathways regulating TAMs have been extensively elucidated, how these cells persistently sense physical properties of the tumor stroma-such as matrix stiffness, tension, and compression-and translate them into sustained immunosuppressive programs remains to be systematically addressed.
MAIN BODY: Unlike other infiltrating immune cell populations that primarily engage in transient adhesive interactions, TAMs utilize integrins for stable spatial anchoring and continuous mechanotransduction. In this review, we synthesize current evidence on the integrin-TAM mechanosensing axis. We first distinguish the persistent mechanobiological features of TAMs from those of structural stromal cells and other transiently infiltrating lymphocytes. Subsequently, we delineate how force-dependent signaling shapes TAM phenotypic plasticity, metabolic reprogramming, and spatial organization. Crucially, we define a self-amplifying biomechanical-immune feedback framework, demonstrating how mechanically remodeled TAMs actively exacerbate extracellular matrix stiffening to consolidate the immunosuppressive niche. Furthermore, we critically evaluate the translational relevance of this axis, analyzing the limitations of past single-target integrin inhibitors and highlighting the emerging potential of multidimensional combination therapeutic strategies.
CONCLUSIONS: Targeting integrin-dependent mechanotransduction provides a rational, system-level strategy to dismantle mechanically reinforced immune barriers. Breaking this interlocking feedback framework offers new insights for remodeling the TME and enhancing the efficacy of current immunotherapies.

Keywords:  Biomechanics; Extracellular matrix; Integrins; Matrix stiffness; Mechanotransduction; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12967-026-08369-7
bioRxiv. 2026 Jul 04. pii: 2026.06.30.735606. [Epub ahead of print]

Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses.

Marwa Saad, Alexandra Thoms, Yue S Yin, Izabela Mamede, Afsana Rahman, Ruonan Chen, Sebastián E Carrasco, Patrick W Darcy, Norihiro Goto, Sohail F Tavazoie, Angelina M Bilate, Daniel Mucida.

Colorectal cancer (CRC) remains a leading cause of cancer mortality, with most cases refractory to immunotherapy. Distinguishing tumor-induced from steady-state mucosal T cell responses has been a critical barrier to understanding antitumor immunity in CRC. Using orthotopic transplantation of CRC organoids with and without metastatic potential, combined with temporal T cell fate-mapping, we show that non-metastatic tumors elicit early recruitment of CD8αβ⁺ and CD4⁺ T cells that acquired cytotoxic and Th1-like programs, whereas pro-metastatic tumors induce a naïve-like, hypoactivated state. Tumor-infiltrating CD4 + T cells underwent clonal expansion, including clones recognizing microbial and dietary antigens. T cells in physical contact with tumor cells, identified by uLIPSTIC, were enriched for expanded and cytotoxic clones. Fate-mapped T cells from non-metastatic tumors suppressed tumor growth in an IFN-γ-dependent manner, whereas pro-metastatic tumor-derived T cells failed to do so. Mechanistically, pro-metastatic tumors downregulated MHCII, and Ciita targeting in non-metastatic organoids reduced CD4⁺ clonal expansion and led to tumor progression. Together, these findings define divergent early T cell trajectories associated with CRC metastatic potential, indicating that ineffective local immune engagement precedes metastatic dissemination.

DOI: https://doi.org/10.64898/2026.06.30.735606
Semin Immunopathol. 2026 07 07. pii: 11. [Epub ahead of print]48(1):

PD-1⁺ CD8⁺ T cells: roles of PD-1 beyond an exhaustion marker.

Jingyi Chen, Zixiang Chen, Liangjie Xu, Jieting Jia, Ke Rui, Jie Tian.

  Programmed cell death protein 1 (PD-1) has long been considered a central molecule in CD8⁺ T cell exhaustion and immunosuppression. However, recent studies have revealed that PD-1⁺CD8⁺ T cells are not a homogeneous population of terminally dysfunctional cells, but rather constitute key immune cells with significant heterogeneity and functional plasticity within tissue immune microenvironments. PD-1 signaling operates throughout multiple stages of CD8⁺ T cell biology, including thymic development, peripheral activation, chronic antigen stimulation, and tissue residency. By finely regulating T cell receptors (TCRs) signal strength, metabolic state, and transcriptional programs, it deeply participates in cell fate decisions while limiting immunopathology. In chronic infections and tumors, persistent antigen stimulation drives PD-1⁺CD8⁺ T cells to form an exhaustion lineage with a defined differentiation hierarchy, encompassing stem-like precursor cells, effector-like transitional cells, and terminally exhausted cells. PD-1 is not only a characteristic marker of this lineage but also a critical regulatory node through which immune checkpoint blockade therapy exerts its therapeutic effects. Furthermore, in contexts such as tissue-resident memory T cells (TRM), GZMK⁺CD8⁺ T cells, and other disease-associated microenvironments, sustained PD-1 expression often represents an adaptive functional regulatory state rather than mere functional inhibition. This review explores the multidimensional regulatory roles of PD-1 in CD8⁺ T cells, with a focus on elucidating the diverse functions and clinical significance of PD-1⁺CD8⁺ T cells in cancer, chronic infections, and autoimmune diseases.

Keywords:  CD8⁺ T cell; GZMK; PD-1; PD-1+ CD8+ TRM ; PD-L1; TRM

DOI:  https://doi.org/10.1007/s00281-026-01078-9
Cancer Control. 2026 Jan-Dec;33:33 10732748261465852

Tumor Microenvironment: The Kingpin in the Emergence of Resistance to Cancer Therapy.

Gaurisankar Sa.



Keywords:  acquired resistance; antitumor immunity; cancer; cancer immunotherapy; cancer stem cell

DOI:  https://doi.org/10.1177/10732748261465852
Adv Pharmacol. 2026 ;pii: S1054-3589(26)00035-9. [Epub ahead of print]106 65-99

T Cell subsets for therapy-unconventional CD1d-restricted natural killer T cells.

Monika Holubová, Valentina Sofia Caputo Galarce, Miroslava Čedíková.

  Unconventional T cells, including gamma delta (γδ) T cells, mucosal-associated invariant T (MAIT) cells, and CD1d-restricted natural killer T (NKT) cells, comprise a unique component of the immune system. These cells play critical roles in host defense, immune regulation, and disease pathogenesis. In particular, invariant NKT (iNKT) cells have emerged as key immunological orchestrators that bridge innate and adaptive immunity by rapidly recognizing lipid antigens presented by CD1d molecules. This chapter provides a comprehensive overview of iNKT cell biology, including their development, phenotypic and functional heterogeneity, and activation mechanisms. It discusses the role of iNKT cells in pathological conditions in detail. Their ability to directly kill tumor cells, as well as their potential to orchestrate the immune response, opens up new possibilities for anti-cancer therapy. Their contribution to immune response regulation and tolerance highlights their critical role in infectious diseases and transplantation. The chapter summarizes current clinical approaches aimed at harnessing iNKT cells, including in vivo activation strategies, adoptive transfer of ex vivo-expanded cells, and developing chimeric antigen receptor (CAR)-engineered iNKT cells. These emerging therapies have advantages over conventional CAR-T approaches, such as reduced toxicity and the potential for allogeneic use. Finally, the chapter discusses the role of type II NKT cells and their cross-regulatory interactions with iNKT cells. Overall, CD1d-restricted NKT cells are a promising target for next-generation immunotherapies. However, further mechanistic and clinical studies are needed to realize their full therapeutic potential.

Keywords:  Adoptive cell therapy; CAR-iNKT therapy; CD1d; Immunomodulation; Invariant natural killer T cells (iNKT); Lipid antigens; Tumor microenvironment; Type II NKT cells; Unconventional T cells

DOI:  https://doi.org/10.1016/bs.apha.2026.05.006
bioRxiv. 2026 Jul 01. pii: 2026.06.28.735129. [Epub ahead of print]

B cell-intrinsic IRF8 transcriptionally reprograms antigen presentation to sustain CD8⁺ T cell antitumor immunity.

Zainab Tiamiyu, Dakota B Poschel, Richa Rashmi, Sergei Bombin, Kendra Fick, Patrick Czabala, Dafeng Yang, Huidong Shi, Keita Saeki, Keiko Ozato, Kebin Liu.

Interferon regulatory factor 8 (IRF8) is a master transcription factor of myeloid differentiation, but whether IRF8 intrinsically controls B cell function in tumors remains unknown. Using paired single-cell transcriptomic and chromatin accessibility profiling of tumors from wild-type and Irf8-deficient mice, we identify a B cell-intrinsic IRF8 axis regulating antigen presentation and sustaining anti-tumor CD8⁺ T cell immunity. IRF8 establishes conserved chromatin accessibility programs across myeloid cells and plasmablasts centered on antigen processing and MHC class I presentation, but engages distinct motifs by lineage: myeloid cells preferentially utilize ISRE and ETS-composite elements, whereas plasmablasts are selectively enriched for EICE elements, reflecting B lineage-specific IRF8-IRF4 cooperation. Loss of IRF8 disrupts these programs, skews B cells toward plasmablast differentiation and reduces antigen presentation machinery. B cell depletion accelerated tumor growth, while CD40 agonism activated B cells, expanded T cells, and enhanced anti-tumor immunity. B cell-specific IRF8 deletion alone accelerated tumor growth, establishing a cell-intrinsic requirement independent of myeloid IRF8 function. The IRF8-regulated B cell signature was enriched in PD-1 blockade cancer patient responders, and plasmablast abundance correlated with response in pembrolizumab-treated cancer patients. These findings establish IRF8 as a lineage-adapted regulator of antigen presentation and define the IRF8-B cell axis as a determinant of anti-tumor immunity.
Highlights: IRF8 establishes a conserved chromatin accessibility across tumor-infiltrating myeloid and B cellsMyeloid cells engage ISRE motifs, whereas plasmablasts rely on EICE motifs as IRF8 lineage-specific cis-regulationIRF8 regulates an antigen presentation in B cells to sustain anti-tumor T cell immunityB cell-intrinsic IRF8 transcription signature predicts patient response to PD-1 blockade immunotherapy.

DOI: https://doi.org/10.64898/2026.06.28.735129
Sci Rep. 2026 Jul 09.

A deep learning model to predict objective response to TACE and TKI-based therapy in HBV-related uHCC.

Zongren Ding, Mengmeng Wu, Zheng Zeng, Guoxu Fang, Zhaodi Huang, Xinling Liu, Zhenwei Chen, Yang Zhou, Yabin Yu, Zisen Lai, Yongyi Zeng.

  TACE and TKI-based combination therapy shows promise for unresectable hepatocellular carcinoma (uHCC), but inter-patient heterogeneity requires reliable biomarkers for personalized management. We developed a deep learning model to predict objective response and progression-free survival (PFS) in HBV-related uHCC. We retrospectively analyzed 243 patients, partitioned into training (clinical n = 168; radiomics n = 106) and test (n = 75) datasets. Three models were constructed: a Clinical Model (C-Model), a Machine Learning Radiomics Model (ML-Model) utilizing 1,479 CT features, and a Deep Learning Model (DL-Model) based on ResNet-50. Model interpretability was addressed via Grad-CAM. Performance was evaluated using AUC and Kaplan-Meier analysis. In the test dataset, the DL-Model achieved a superior AUC of 0.851 (95% CI: 0.747-0.954), significantly outperforming the C-Model (AUC = 0.586, P < 0.05) and exceeding the ML-Model (AUC = 0.709). Survival analysis showed the DL-Model was the only framework capable of robust prognostic stratification; predicted responders had significantly prolonged PFS (P = 0.011). Grad-CAM analysis revealed a spatial dichotomy: responders exhibited focal, centralized tumor activation, whereas non-responders showed multifocal, peripheral activation patterns. The DL-Model provides a reliable, interpretable tool for predicting tumor response and PFS in uHCC patients receiving TACE and TKI-based therapy. The Grad-CAM visualization offers spatial insights into tumor heterogeneity, facilitating personalized treatment adjustments.

Keywords:  Deep learning; Grad-CAM; Hepatocellular carcinoma; Objective response; Radiomics

DOI:  https://doi.org/10.1038/s41598-026-60928-6
Nat Immunol. 2026 Jul 07.

Tissue-resident CD8+ T cells link pregnancy to breast cancer protection.

DOI: https://doi.org/10.1038/s41590-026-02580-w
Nat Genet. 2026 Jul 08.

Metabolically and epigenetically reprogrammed splenic TRNP1hiCD8+ T cells exacerbate liver fibrosis.

Liyuan Zhang, Yahui Wang, Kai Wei, Wen Nie, Yayuan Feng, Zhiwen Shi, Hongmei Xiao, Weifen Xie, Yong Lin, Xin Zeng, Yongquan Shi, Wei Tang, Tuo Li, Fu Yang, Ye Zhou, Minjun Wang, Yanfang Liu, Shanrong Liu, Jin Hou.

Metabolic dysfunction-associated steatotic liver disease (MASLD), especially its severe form, metabolic dysfunction-associated steatohepatitis (MASH), progresses to liver fibrosis, leading to cirrhosis and liver cancer. The cross-talk between spleen and liver in MASLD/MASH progression remains poorly understood. Here we found enlarged spleens in patients with MASLD and identified induced TRNP1hiCD8+ T cells in spleens of MASLD/MASH mouse models and patients. These cells exhibited pro-fibrotic properties through secretion of INSR-α. Mechanistically, demethylated DNA and H3K27me3, increased H3K27ac and bolstered enhancer-promoter contact synergistically reorganized chromatin topologically associating domains spatially to initiate the expression of transcription factor TRNP1 in splenic CD8+ T cells. TRNP1 then transcriptionally activated the expression of FURIN and CTSD, promoting the maturation and ectodomain shedding of INSR-α and facilitating its secretion to activate hepatic stellate cells. In vivo blockade of INSR-α using neutralizing antibodies alleviated MASLD/MASH-induced liver fibrosis. This study reveals splenic TRNP1hiCD8+ T cells with pro-fibrotic properties and suggests a potential anti-fibrotic strategy.

DOI: https://doi.org/10.1038/s41588-026-02660-5
Clin Transl Gastroenterol. 2026 Jul 06.

Beyond the Count: Critical Gaps in Intraepithelial Lymphocyte-Based Progression Markers of Potential Autoimmune Gastritis.

Abdul Qayum Khan, Tabasum Shehzadi, Abdul Wahab, Salman Khan, Rabia Asghar Khattak.



Keywords:  Immunophenotyping; Intraepithelial T lymphocytes; Pepsinogen I/II ratio; Potential autoimmune gastritis; Prognostic biomarkers

DOI:  https://doi.org/10.14309/ctg.0000000000001073
J Exp Clin Cancer Res. 2026 Jul 10.

Suppression of the myofibroblastic cancer-associated fibroblast phenotype to enhance anti-PD-1 response.

Katherine A Johnson, Anna E L Lippert, Alec Cornelio, Yousef Gadalla, Xingqi Shen, Sean G Kraus, Philip B Emmerich, Anna M Field, Alyssa K Steimle, Cheri A Pasch, Huy Q Dinh, Wei Zhang, Kristina A Matkowskyj, Dustin A Deming.

   BACKGROUND: Cancer-associated fibroblasts (CAFs) are key modulators of tumor growth, the tumor immune context, and treatment response. CAFs take on diverse phenotypes with distinct functions. Myofibroblastic CAFs (myCAFs) regulate extracellular matrix remodeling, while inflammatory CAFs (iCAFs) modulate immune infiltration. Further studies are required to validate biomarkers of CAF phenotypes and to identify means to therapeutically manipulate CAFs.
METHODS: Single-cell RNA sequencing analysis was used to identify markers of CAF phenotypes in CRC. CAF markers were validated and compared to clinical characteristics using patient-derived CAF cultures, fixed human CRC samples, and publicly available RNA sequencing data. Therapeutics were prioritized for their potential to inhibit the myCAF phenotype and nilotinib was selected for validation in patient-derived CAFs. Overall changes in CAFs were evaluated via RNA-seq, and results validated with in vitro experiments. Finally, the feasibility of altering CAF phenotypes to affect treatment response was evaluated in vivo.
RESULTS: Here we identify disease-specific markers of colorectal CAFs that are functionally distinct, biologically identifiable, correlate with clinically relevant markers of disease, and can be therapeutically altered in vivo. High stromal expression of myCAF markers correlated with reduced infiltration of CD8+ T lymphocytes into the epithelial compartment compared to tumors with high stromal expression of iCAF markers. Nilotinib treatment inhibited myogenesis regulators myocardin and myocardin-related transcription factor A, which correlated with reduced expression of myCAF markers and extracellular matrix proteins and decreased tumor size in colorectal cancer-bearing mice when combined with anti-PD-1 therapy. We also identified PD-1 as a potential molecule that activates myocardin and myCAF expression, indicating a potential mechanism for increased response to the combination with anti-PD-1 therapy.
CONCLUSIONS: These results highlight the feasibility of targeting CAF functions to improve therapeutic response, and support the investigation of nilotinib and anti-PD-1 therapy clinically.

Keywords:  Anti-PD-1; Cancer-associated fibroblasts; Colorectal cancer; Myocardin; Nilotinib; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-026-03779-3
bioRxiv. 2026 Jul 01. pii: 2026.06.28.735088. [Epub ahead of print]

Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation.

Grace E Crossland, Andre Armero, Vianey Chavez, Zachary T Peters, Lennard Ostendorf, Shriya Kannan, Lindsay K Mendyka, Olivia F Brooker, Kaitlyn Dowling, Himanshu B Goswami, Dorothea Barton, Sonia Leach, Fred W Kolling, Pamela C Rosato, Mark S Sundrud, Theresa T Lu, Deepak A Rao, Michael G Constantinides, Sladjana Skopelja-Gardner.

Mucosal-associated invariant T (MAIT) cells are enriched at barrier sites, but their role in autoimmune skin inflammation remains unknown. Using cutaneous lupus as a model, we identify MAIT cells as protective regulators of skin inflammation and as critical upstream modulators of regulatory T cells (Treg). Topical MAIT cell activation with 5-OP-RU induced durable resolution of spontaneous skin lesions in MRL/lpr mice and suppressed TLR7-driven skin inflammation. MAIT cell activation selectively expanded and activated Treg populations in both healthy and lupus-like skin, while suppressing effector T cell cytokine production and cytotoxic programs. This MAIT-Treg axis was also activated in UV light-driven barrier injury in healthy murine and human skin, where MAIT cells were required for UV-elicited Treg expansion and function. In lupus-like skin, local MAIT cell activation restored the defective UVB-induced Treg response and limited CD8+ T cell expansion. Mechanistically, CCR2+ monocyte-derived antigen-presenting cells and IL-15 signaling were required for MAIT cell-driven Treg accumulation and therapeutic benefits of MAIT cells in inflamed skin. These studies identify a MAIT-IL-15-Treg axis that links barrier injury sensing to immune regulation, which is disrupted in cutaneous lupus, and nominate therapeutic MAIT cell activation as an unappreciated strategy for restoring immune homeostasis in inflamed skin.

DOI: https://doi.org/10.64898/2026.06.28.735088