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Deep learning and inflammatory markers predict early response to immunotherapy in unresectable NSCLC: A multicenter study

Biomol Biomed. 2025 Jun 10. doi: 10.17305/bb.2025.12324. Online ahead of print.

ABSTRACT

Immune checkpoint inhibitors (ICIs) demonstrate substantial interpatient variability in clinical efficacy for unresectable non-small cell lung cancer (NSCLC), underscoring the unmet need for noninvasive biomarkers to predict early therapeutic responses and improve survival outcomes. To address this, we developed a CT-based deep learning model integrated with the systemic immune-inflammatory-nutritional index (SIINI) for early prediction of ICI response. In a retrospective multicenter study of 265 patients treated with ICIs (incorporating chest CT and laboratory data), the cohort was divided into training (70%), internal validation (30%), and external validation sets. The combined model-leveraging DenseNet121-derived deep radiomic features alongside SIINI-achieved strong predictive performance, with AUCs of 0.865 (95% CI: 0.7709-0.9595) in the internal validation cohort and 0.823 (95% CI: 0.6627-0.9827) in the external validation cohort. Gradient-weighted class activation mapping (Grad-CAM) highlighted key CT regions contributing to model predictions, enhancing interpretability for clinical application. These findings highlight the potential of integrating deep learning with inflammatory biomarkers to support personalized ICI therapy in unresectable NSCLC. Future directions include incorporating multi-omics biomarkers, expanding multicenter validation, and increasing sample sizes to further improve predictive accuracy and facilitate clinical translation.

PMID:40525631 | DOI:10.17305/bb.2025.12324

  • ✇36氪
  • 红杉中国正式开源AI基准测试xbench评测集
    6月18日,红杉中国正式开源其AI基准测试工具xbench的两个评测集xbench-ScienceQA和xbench-DeepSearch。红杉中国表示,未来将基于大模型和AI Agent的发展情况不断动态更新评测集,并且采用“黑白盒”机制,既保证xbench的发展可以服务更多的大模型和Agent开发者,同时尽力避免静态评测集经常出现的过拟合问题,确保xbench的长期有效。(界面)
     

红杉中国正式开源AI基准测试xbench评测集

18 June 2025 at 08:37
6月18日,红杉中国正式开源其AI基准测试工具xbench的两个评测集xbench-ScienceQA和xbench-DeepSearch。红杉中国表示,未来将基于大模型和AI Agent的发展情况不断动态更新评测集,并且采用“黑白盒”机制,既保证xbench的发展可以服务更多的大模型和Agent开发者,同时尽力避免静态评测集经常出现的过拟合问题,确保xbench的长期有效。(界面)
  • ✇MIT Technology Review
  • AI copyright anxiety will hold back creativity Nitin Nohria
    Last fall, while attending a board meeting in Amsterdam, I had a few free hours and made an impromptu visit to the Van Gogh Museum. I often steal time for visits like this—a perk of global business travel for which I am grateful. Wandering the galleries, I found myself before The Courtesan (after Eisen), painted in 1887. Van Gogh had based it on a Japanese woodblock print by Keisai Eisen, which he encountered in the magazine Paris Illustré. He explicitly copied and reinterpreted Eisen’s composit
     

AI copyright anxiety will hold back creativity

17 June 2025 at 18:00

Last fall, while attending a board meeting in Amsterdam, I had a few free hours and made an impromptu visit to the Van Gogh Museum. I often steal time for visits like this—a perk of global business travel for which I am grateful. Wandering the galleries, I found myself before The Courtesan (after Eisen), painted in 1887. Van Gogh had based it on a Japanese woodblock print by Keisai Eisen, which he encountered in the magazine Paris Illustré. He explicitly copied and reinterpreted Eisen’s composition, adding his own vivid border of frogs, cranes, and bamboo.

As I stood there, I imagined the painting as the product of a generative AI model prompted with the query How would van Gogh reinterpret a Japanese woodblock in the style of Keisai Eisen? And I wondered: If van Gogh had used such an AI tool to stimulate his imagination, would Eisen—or his heirs—have had a strong legal claim?  If van Gogh were working today, that might be the case. Two years ago, the US Supreme Court found that Andy Warhol had infringed upon the photographer Lynn Goldsmith’s copyright by using her photo of the musician Prince for a series of silkscreens. The court said the works were not sufficiently transformative to constitute fair use—a provision in the law that allows for others to make limited use of copyrighted material.

A few months later, at the Museum of Fine Arts in Boston, I visited a Salvador Dalí exhibition. I had always thought of Dalí as a true original genius who conjured surreal visions out of thin air. But the show included several Dutch engravings, including Pieter Bruegel the Elder’s Seven Deadly Sins (1558), that clearly influenced Dalí’s 8 Mortal Sins Suite (1966). The stylistic differences are significant, but the lineage is undeniable. Dalí himself cited Bruegel as a surrealist forerunner, someone who tapped into the same dream logic and bizarre forms that Dalí celebrated. Suddenly, I was seeing Dalí not just as an original but also as a reinterpreter. Should Bruegel have been flattered that Dalí built on his work—or should he have sued him for making it so “grotesque”?

During a later visit to a Picasso exhibit in Milan, I came across a famous informational diagram by the art historian Alfred Barr, mapping how modernist movements like Cubism evolved from earlier artistic traditions. Picasso is often held up as one of modern art’s most original and influential figures, but Barr’s chart made plain the many artists he drew from—Goya, El Greco, Cézanne, African sculptors. This made me wonder: If a generative AI model had been fed all those inputs, might it have produced Cubism? Could it have generated the next great artistic “breakthrough”?

These experiences—spread across three cities and centered on three iconic artists—coalesced into a broader reflection I’d already begun. I had recently spoken with Daniel Ek, the founder of Spotify, about how restrictive copyright laws are in music. Song arrangements and lyrics enjoy longer protection than many pharmaceutical patents. Ek sits at the leading edge of this debate, and he observed that generative AI already produces an astonishing range of music. Some of it is good. Much of it is terrible. But nearly all of it borrows from the patterns and structures of existing work.

Musicians already routinely sue one another for borrowing from previous works. How will the law adapt to a form of artistry that’s driven by prompts and precedent, built entirely on a corpus of existing material?

And the questions don’t stop there. Who, exactly, owns the outputs of a generative model? The user who crafted the prompt? The developer who built the model? The artists whose works were ingested to train it? Will the social forces that shape artistic standing—critics, curators, tastemakers—still hold sway? Or will a new, AI-era hierarchy emerge? If every artist has always borrowed from others, is AI’s generative recombination really so different? And in such a litigious culture, how long can copyright law hold its current form? The US Copyright Office has begun to tackle the thorny issues of ownership and says that generative outputs can be copyrighted if they are sufficiently human-authored. But it is playing catch-up in a rapidly evolving field. 

Different industries are responding in different ways. The Academy of Motion Picture Arts and Sciences recently announced that filmmakers’ use of generative AI would not disqualify them from Oscar contention—and that they wouldn’t be required to disclose when they’d used the technology. Several acclaimed films, including Oscar winner The Brutalist, incorporated AI into their production processes.

The music world, meanwhile, continues to wrestle with its definitions of originality. Consider the recent lawsuit against Ed Sheeran. In 2016, he was sued by the heirs of Ed Townsend, co-writer of Marvin Gaye’s “Let’s Get It On,” who claimed that Sheeran’s “Thinking Out Loud” copied the earlier song’s melody, harmony, and rhythm. When the case finally went to trial in 2023, Sheeran brought a guitar to the stand. He played the disputed four-chord progression—I–iii–IV–V—and wove together a mash-up of songs built on the same foundation. The point was clear: These are the elemental units of songwriting. After a brief deliberation, the jury found Sheeran not liable.

Reflecting after the trial, Sheeran said: “These chords are common building blocks … No one owns them or the way they’re played, in the same way no one owns the colour blue.”

Exactly. Whether it’s expressed with a guitar, a paintbrush, or a generative algorithm, creativity has always been built on what came before.

I don’t consider this essay to be great art. But I should be transparent: I relied extensively on ChatGPT while drafting it. I began with a rough outline, notes typed on my phone in museum galleries, and transcripts from conversations with colleagues. I uploaded older writing samples to give the model a sense of my voice. Then I used the tool to shape a draft, which I revised repeatedly—by hand and with help from an editor—over several weeks.

There may still be phrases or sentences in here that came directly from the model. But I’ve iterated so much that I no longer know which ones. Nor, I suspect, could any reader—or any AI detector. (In fact, Grammarly found that 0% of this text appeared to be AI-generated.)

Many people today remain uneasy about using these tools. They worry it’s cheating, or feel embarrassed to admit that they’ve sought such help. I’ve moved past that. I assume all my students at Harvard Business School are using AI. I assume most academic research begins with literature scanned and synthesized by these models. And I assume that many of the essays I now read in leading publications were shaped, at least in part, by generative tools.

Why? Because we are professionals. And professionals adopt efficiency tools early. Generative AI joins a long lineage that includes the word processor, the search engine, and editing tools like Grammarly. The question is no longer Who’s using AI? but Why wouldn’t you?

I recognize the counterargument, notably put forward by Nicholas Thompson, CEO of the Atlantic: that content produced with AI assistance should not be eligible for copyright protection, because it blurs the boundaries of authorship. I understand the instinct. AI recombines vast corpora of preexisting work, and the results can feel derivative or machine-like.

But when I reflect on the history of creativity—van Gogh reworking Eisen, Dalí channeling Bruegel, Sheeran defending common musical DNA—I’m reminded that recombination has always been central to creation. The economist Joseph Schumpeter famously wrote that innovation is less about invention than “the novel reassembly of existing ideas.” If we tried to trace and assign ownership to every prior influence, we’d grind creativity to a halt.

From the outset, I knew the tools had transformative potential. What I underestimated was how quickly they would become ubiquitous across industries and in my own daily work.

Our copyright system has never required total originality. It demands meaningful human input. That standard should apply in the age of AI as well. When people thoughtfully engage with these models—choosing prompts, curating inputs, shaping the results—they are creating. The medium has changed, but the impulse remains the same: to build something new from the materials we inherit.


Nitin Nohria is the George F. Baker Jr. Professor at Harvard Business School and its former dean. He is also the chair of Thrive Capital, an early investor in several prominent AI firms, including OpenAI.

MIT Technology Review’s editorial guidelines state that generative AI should not be used to draft articles unless the article is meant to illustrate the capabilities of such tools and its use is clearly disclosed. 

Next-generation cancer therapeutics: unveiling the potential of liposome-based nanoparticles through bioinformatics

Mikrochim Acta. 2025 Jun 16;192(7):428. doi: 10.1007/s00604-025-07286-8.

ABSTRACT

Cancer remains one of the most deadly diseases in the world, requiring constant growth and improvements in therapeutic strategies. Traditional cancer treatments, such as chemotherapy, radiotherapy, and surgery, have limitations like off-target release, toxicity, and inefficient drug delivery. This study explains the role of bioinformatics and AI in optimizing and analyzing liposomal formulations for innovative and better cancer therapy. Molecular docking (MD), molecular dynamics simulations, and machine learning models are the computational techniques that can help to design stable liposomal carriers for drugs, predict receptor-ligand interactions, and can improve drug release efficiency. Improved liposome nanoparticles (LNPs) surface functionalization, the discovery of tumor-specific biomarkers, and the improvement of receptor-ligand interactions for accurate drug targeting are all made possible by bioinformatics tools and methodologies. Moreover, AI-assisted predictions and in silico modeling can speed up drug discovery and processing while eliminating the experimental expenditures and time. In the present review, we conducted MD studies to complement the discussed literature. MD was performed between cyclic RGD peptides (liposomal ligands) and the GPR116 receptor in triple-negative breast cancer, and between folic acid (liposomal ligand) and the Axl tyrosine kinase receptor for lung cancer, revealing strong and stable interactions and highlighting the amino acid residues involved. Notwithstanding current obstacles, computational tools have shown notable progress in nanomedicine, exploring more options for more individualized and effective cancer therapies. The combination of AI, machine learning, and multi-omics techniques to improve therapeutic efficacy and reduce side effects is a substantial key to the future of LNP-based cancer treatment.

PMID:40523994 | DOI:10.1007/s00604-025-07286-8

  • ✇36氪
  • “夸克老师”上线,AI首次具备个性化辅导能力
    6月17日,夸克App推出全新升级的学习产品“夸克老师”——一位能够讲题、批作业、出题、找试卷的AI家教。产品最大的特点是能够因材施教,基于学生的历史情况进行指导,还能提供个性化的练习。该模型以通义千问为基础,运用指令微调、强化学习以及讲解复杂度奖励等前沿方法训练。模型尤其在解答数学、物理等高难度题目时,展现出了卓越的推理及讲解能力。
     

“夸克老师”上线,AI首次具备个性化辅导能力

17 June 2025 at 14:05
6月17日,夸克App推出全新升级的学习产品“夸克老师”——一位能够讲题、批作业、出题、找试卷的AI家教。产品最大的特点是能够因材施教,基于学生的历史情况进行指导,还能提供个性化的练习。该模型以通义千问为基础,运用指令微调、强化学习以及讲解复杂度奖励等前沿方法训练。模型尤其在解答数学、物理等高难度题目时,展现出了卓越的推理及讲解能力。

Association between pace of biological aging and cancer and the modulating role of physical activity: a national cross-sectional study

Cancer remains a serious public health problem impeding gains in life expectancy. Epigenetic clocks, derived from sets of DNA methylation CpGs and mathematical algorithms, have demonstrated a remarkable abilit...

Mendelian randomization in cancer research: opportunities and challenges

Infect Agent Cancer. 2025 Jun 15;20(1):37. doi: 10.1186/s13027-025-00672-0.

ABSTRACT

Mendelian Randomization (MR) is increasingly used in cancer research to infer causal relationships by leveraging genetic variants as instrumental variables. While the growth of genome-wide association studies and biobank data has expanded the utility of MR, this surge-particularly pronounced in China-raises concerns about methodological rigor. The widespread adoption may be partly driven by the Chinese translation of key MR literature. Recent advances such as multivariable MR, mediation analysis, and integration with AI and omics data have enhanced the robustness and biological interpretability of MR studies. However, challenges persist, including horizontal pleiotropy, weak instrument bias, and misinterpretation of biomarkers as causal exposures. To improve MR study credibility, frameworks like STROBE-MR and MR-GRADE are being adopted. This article reviews methodological improvements and persistent pitfalls in MR, especially within cancer epidemiology, and highlights strategies for ensuring validity in this rapidly evolving field.

PMID:40518507 | PMC:PMC12168377 | DOI:10.1186/s13027-025-00672-0

A multi-phase approach using supervised algorithms and clinical models to generate high-accuracy signatures for pancreatic cancer

Comput Biol Med. 2025 Aug;194:110559. doi: 10.1016/j.compbiomed.2025.110559. Epub 2025 Jun 14.

ABSTRACT

BACKGROUND: The in silico analyses provide evidence supporting the potential of methylation-driven differentially expressed genes as therapeutic targets across cancer types. This leads us to identify novel targets and their associated drug compounds for further progress towards pancreatic cancer treatment.

OBJECTIVE: To identify targeted drugs based on methylation driven genes identified using bulk multi-omics data and single-cell level data to pinpoint important disease markers.

METHODS: The workflow involves screening using the TCGA and ICGC databases, followed by validation with GEO datasets. The study employs supervised learning algorithms like kNN and random forests, and constructs a prediction model using adaptive LASSO-Cox regression. The process also includes pathway analysis, evaluation of survival status, and immune profile deconvolution, as well as multistage evaluation of the methylation driven genes. We conducted drug targeting and molecular dynamic simulations, taking into account genes of interest.Lastly, molecular docking and dynamics simulations were used to find out if the key MEDEGs could be utilized as drug targets.

RESULTS: CD36, UGT1A1, TFF1, S100P, MUC13, CALHM3 and ANKRD44 were found to be top 7 methylation driven genes. The mutational profile was also documented along with pathway analysis, which showed concordance with our observation based on their significant enriched terms namely "Maintenance of Gastrointestinal Epithelium", and "Digestive System Homeostasis". CD36 had prognostic capabilities and was seen to significant in terms of survival and also showed significant immune dysregulation. Our novel findings suggest TFF1, S100P, and MUC13 were found to be associated with cell type specific expression as seen in single cell data and UGT1A1 was found to be suitable for probable drug targeting. CD36, UGT1A1, TFF1, S100P, and MUC13 showed concordance when observed at proteomics level and across other datasets. Apigenin-7-O-glucuronide emerged as the top binder for UDP-glucuronosyltransferase 1A1 (also known as UDP 1A1), forming stable complexes with favourable interactions. Catechin and epicatechin were identified as the best ligands for TFF1 and S100P, while rutin showed high-affinity binding to MUC13.

CONCLUSION: The study successfully identified and validated a panel of biomarkers specific to pancreatic cancer, with potential applications in early diagnosis and treatment. The findings highlight the importance of multi-omics data integration in cancer research and the potential of personalized medicine in improving patient outcomes. The in-silico drug targeting analysis provides a foundation for the development of novel drugs for PanCa treatment. Hence TFF1, S100P, MUC13, and UGT1A1 showcased themselves as most promising biomarkers and novel drug targets.

PMID:40517592 | DOI:10.1016/j.compbiomed.2025.110559

  • ✇MIT Technology Review
  • The Download: how AI can improve a city, and inside OpenAI’s empire Rhiannon Williams
    This is today’s edition of The Download, our weekday newsletter that provides a daily dose of what’s going on in the world of technology. How AI can help make cities work better In recent decades, cities have become increasingly adept at amassing all sorts of data. But that data can have limited impact when government officials are unable to communicate, let alone analyze or put to use, all the information they have access to.This dynamic has always bothered Sarah Williams, a professor of
     

The Download: how AI can improve a city, and inside OpenAI’s empire

16 June 2025 at 20:10

This is today’s edition of The Download, our weekday newsletter that provides a daily dose of what’s going on in the world of technology.

How AI can help make cities work better

In recent decades, cities have become increasingly adept at amassing all sorts of data. But that data can have limited impact when government officials are unable to communicate, let alone analyze or put to use, all the information they have access to.

This dynamic has always bothered Sarah Williams, a professor of urban planning and technology at MIT. Shortly after joining MIT in 2012, Williams created the Civic Data Design Lab to bridge that divide. Over the years, she and her colleagues have made urban planning data more vivid and accessible through human stories and striking graphics. Read the full story.

—Ben Schneider

This story is from the next print edition of MIT Technology Review, which explores power—who has it, and who wants it. It’s set to go live on Wednesday June 25, so subscribe & save 25% to read it and get a copy of the issue when it lands!

Inside OpenAI’s empire with Karen Hao

AI journalist Karen Hao’s newly released book, Empire of AI: Dreams and Nightmares in Sam Altman’s OpenAI, tells the story of OpenAI’s rise to power and its far-reaching impact all over the world.

Hao, a former MIT Technology Review senior editor, will join our executive editor Niall Firth in an intimate subscriber-exclusive Roundtable conversation exploring the AI arms race, what it means for all of us, and where it’s headed. Register here to join us at 9am ET on Monday June 30th June.

Special giveaway: Attendees will have the chance to receive a free copy of Hao’s book. See registration form for details.

The must-reads

I’ve combed the internet to find you today’s most fun/important/scary/fascinating stories about technology.

1 The White House is sharing tasteless deportation memes
Its digital strategy revolves around boosting policies for cheap laughs. (WP $)
+ Trump’s immigration raids are a rapid escalation of his deportation tactics. (Vox)
+ The administration is revelling in the outraged reaction to its actions. (The Atlantic $)
+ But New Yorkers are fighting back. (New Yorker $)

2 New York is asking companies to disclose when AI contributes to layoffs
It’s the first official step towards measuring AI’s impact on the labor market. (Bloomberg $)
+ People are worried that AI will take everyone’s jobs. We’ve been here before. (MIT Technology Review)

3 Regeneron isn’t buying 23andMe after all
A non-profit controlled by its cofounder has made a higher bid. (WSJ $)
+ Anne Wojcicki says she has the backing of a Fortune 500 company. (FT $)
+ How to… delete your 23andMe data. (MIT Technology Review)

4 RFK Jr has filled the CDC’s vaccine committee with allies
Robert Malone, one of the appointees, has encouraged the public to embrace the term anti-vax. (The Atlantic $)
+ Here’s what food and drug regulation might look like under the Trump administration. (MIT Technology Review)

5 Americans are commissioning animal torture videos
The US government has revealed details of residents accused of paying people in Indonesia to abuse helpless monkeys. (Ars Technica)

6 China has conducted its first brain implant clinical trial
Making it only the second country to do so, after the US. (Bloomberg $)
+ Brain-computer interfaces face a critical test. (MIT Technology Review)

7 The US Navy wants your startup
It’s more open to partnerships than ever before, apparently. (TechCrunch)
+ China is stockpiling intercontinental ballistic missiles. (Insider $)
+ Generative AI is learning to spy for the US military. (MIT Technology Review)

8 The UK is working on a chemotherapy-free approach to treating leukaemia
Combining two targeted drugs appears to perform better. (The Guardian)

9 Brace yourself for AI sponcon
Just when you thought product placement couldn’t get any worse. (The Verge)

10 Zines are staging a comeback
Creatives are turning their backs on social media in favor of good old-fashioned booklets. (Wired $)

Quote of the day

“Being a highly “online” person is a very embarrassing thing and should be relegated to basement losers.”

—Derek Guy, aka The Menswear Guy on X, explains to Wired why he thinks a significant proportion of the Republican coalition need to step away from their keyboards.

One more thing

Bright LEDs could spell the end of dark skies

Scientists have known for years that light pollution is growing and can harm both humans and wildlife. In people, increased exposure to light at night disrupts sleep cycles and has been linked to cancer and cardiovascular disease, while wildlife suffers from interruption to their reproductive patterns, and increased danger.

Astronomers, policymakers, and lighting professionals are all working to find ways to reduce light pollution. Many of them advocate installing light-emitting diodes, or LEDs, in outdoor fixtures such as city streetlights, mainly for their ability to direct light to a targeted area.

But the high initial investment and durability of modern LEDs mean cities need to get the transition right the first time or potentially face decades of consequences. Read the full story.

—Shel Evergreen

We can still have nice things

A place for comfort, fun and distraction to brighten up your day. (Got any ideas? Drop me a line or skeet ’em at me.)

+ As commencement speeches go, Steve Jobs’ is definitely one of the best.
+ I love this iconic Homer moment recreated in Lego.
+ The remains of a beautiful Byzantine tomb complex has been uncovered between Aleppo and Damascus.
+ I want to believe: check out this short, bizarre history of alien abductions in America 👽

Advances in molecular pathology and therapy of non-small cell lung cancer

Signal Transduct Target Ther. 2025 Jun 15;10(1):186. doi: 10.1038/s41392-025-02243-6.

ABSTRACT

Over the past two decades, non-small cell lung cancer (NSCLC) has witnessed encouraging advancements in basic and clinical research. However, substantial unmet needs remain for patients worldwide, as drug resistance persists as an inevitable reality. Meanwhile, the journey towards amplifying the breadth and depth of the therapeutic effect requires comprehending and integrating diverse and profound progress. In this review, therefore, we aim to comprehensively present such progress that spans the various aspects of molecular pathology, encompassing elucidations of metastatic mechanisms, identification of therapeutic targets, and dissection of spatial omics. Additionally, we also highlight the numerous small molecule and antibody drugs, encompassing their application alone or in combination, across later-line, frontline, neoadjuvant or adjuvant settings. Then, we elaborate on drug resistance mechanisms, mainly involving targeted therapies and immunotherapies, revealed by our proposed theoretical models to clarify interactions between cancer cells and a variety of non-malignant cells, as well as almost all the biological regulatory pathways. Finally, we outline mechanistic perspectives to pursue innovative treatments of NSCLC, through leveraging artificial intelligence to incorporate the latest insights into the design of finely-tuned, biomarker-driven combination strategies. This review not only provides an overview of the various strategies of how to reshape available armamentarium, but also illustrates an example of clinical translation of how to develop novel targeted drugs, to revolutionize therapeutic landscape for NSCLC.

PMID:40517166 | PMC:PMC12167388 | DOI:10.1038/s41392-025-02243-6

A multi-omics and mediation-based genetic screening approach identifies STX4 as a key link between epigenetic regulation, immune cells, and childhood asthma

Childhood asthma presents a multifaceted immune-driven pathology shaped by genetic, epigenetic, and immune regulatory interactions. Despite extensive genome-wide analyses pinpointing multiple susceptibility lo...

Integrated multi-omics analysis and experimental investigation of mitochondrial dynamics-related genes: molecular subtypes, immune landscape, and prognostic implications in lung adenocarcinoma

Front Immunol. 2025 May 29;16:1585505. doi: 10.3389/fimmu.2025.1585505. eCollection 2025.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is a common and aggressive subtype of lung cancer associated with poor clinical outcomes. The role of mitochondrial dynamics (MD)-related genes in tumor progression and immune regulation remains poorly understood.

METHODS: Data from public databases were integrated, and subtypes were classified based on 23 MD-related genes. A five-gene prognostic model was constructed. Associations between the model and immune infiltration, tumor mutational burden (TMB), tumor stemness, and drug sensitivity were analyzed. The function of the key gene MTCH2 was validated through in vitro experiments.

RESULTS: Two distinct MD molecular subtypes were identified, exhibiting significant differences in prognosis and immune characteristics. A corresponding risk score model was established. Patients in the low-risk group showed better prognosis and enhanced immune activity, whereas the high-risk group displayed higher TMB and stemness scores. Drug sensitivity analysis revealed distinct responses to chemotherapeutic agents such as cisplatin and docetaxel between risk groups. Functional assays demonstrated that MTCH2 knockout significantly inhibited LUAD cell proliferation, migration, and invasion, and induced G0/G1 phase arrest, suggesting that MTCH2 may act as a potential adverse prognostic marker.

CONCLUSION: MD-related genes exhibit strong prognostic and immune subtyping value. The proposed risk model holds clinical potential, and MTCH2 may serve as a promising target for precision therapy in LUAD.

PMID:40510359 | PMC:PMC12159055 | DOI:10.3389/fimmu.2025.1585505

Cancer gene identification from RNA variant allelic frequencies using RVdriver

Genome Biol. 2025 Jun 13;26(1):165. doi: 10.1186/s13059-025-03557-y.

ABSTRACT

Existing approaches to identifying cancer genes rely overwhelmingly on DNA sequencing data. Here, we introduce RVdriver, a computational tool that leverages paired bulk genomic and transcriptomic data to classify RNA variant allele frequencies (VAFs) of non-synonymous mutations relative to a synonymous mutation background. We analyze 7882 paired exomes and transcriptomes from 31 cancer types and identify novel, as well as known, cancer genes, complementing other DNA-based approaches. Furthermore, RNA VAFs of individual mutations are able to distinguish "driver" from "passenger" mutations within established cancer genes. This approach highlights the value of multi-omic approaches for cancer gene discovery.

PMID:40514689 | PMC:PMC12164115 | DOI:10.1186/s13059-025-03557-y

Integrative multi-omics profiling deciphers tumor microenvironment heterogeneity and immunotherapy vulnerabilities in lung neuroendocrine carcinomas

J Adv Res. 2025 Jun 11:S2090-1232(25)00427-8. doi: 10.1016/j.jare.2025.06.017. Online ahead of print.

ABSTRACT

INTRODUCTION: Lung neuroendocrine carcinomas (Lu-NECs) are rare, highly aggressive lung tumors with poor prognosis and limited therapeutic options. Understanding the tumor immune microenvironment (TIME) is crucial towards personalized therapeutic strategies.

OBJECTIVES: This study aims to systematically characterize the heterogeneity and complexity of the TIME in Lu-NECs by integrating proteomic, transcriptomic, and genomic data.

METHODS: We performed comprehensive immune-proteomic profiling of 76 Lu-NECs across diverse histopathological subtypes to elucidate intra-tumoral TIME heterogeneity at the proteomic level. Validation was conducted in multiple independent cohorts, including 112 Lu-NECs using immunohistochemistry, 147 Lu-NECs, and 17 small cell lung carcinoma samples using transcriptomics. We integrated proteomic, transcriptomic, genomic, and clinical data to assess molecular, immunological, and clinical features, as well as therapeutic vulnerabilities across different immune subtypes.

RESULTS: We delineated the immuno-proteomic landscape of Lu-NECs and identified two major immuno-proteomic clusters with distinct immunological, molecular, and clinical characteristics. IPC1 was characterized by high immune cell infiltration, while IPC2 exhibited sparse immune cell presence. Genomic analysis revealed distinct mutational patterns, with IPC1 showing a higher incidence of APOBEC-associated mutation signatures and IPC2 being enriched for mutations associated with defective DNA mismatch repair and tobacco-related mutagens. Functional analyses indicated that IPC1 was related to immune and oncogenic signaling activity, whereas IPC2 was associated with cancer stemness and proliferation-related features. Furthermore, IPC1 and IPC2 demonstrated histological subtype-specific clinical benefits from postoperative chemotherapy. Finally, we developed a machine learning model (iPROM) to predict Lu-NECs immune classification and improve risk stratification, which was validated across multiple independent cohorts.

CONCLUSIONS: This study advances the understanding of the tumor immune microenvironment in Lu-NECs through multi-omics characterization and highlights potential personalized therapeutic vulnerabilities tailored to the specific immune landscapes of Lu-NECs.

PMID:40513660 | DOI:10.1016/j.jare.2025.06.017

An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer

Cell Stem Cell. 2025 Jun 6:S1934-5909(25)00191-2. doi: 10.1016/j.stem.2025.05.011. Online ahead of print.

ABSTRACT

Deciphering interactions between tumor micro- and systemic immune macroenvironments is essential for developing more effective cancer diagnosis and therapeutic strategies. Here, we established a gel-liquid interface (GLI) co-culture model of lung cancer organoids (LCOs) and paired peripheral-blood mononuclear cells (PBMCs), featuring enhanced interactions between immune cells and tumor organoids for optimized simulation of in vivo systemic anti-tumor immunity. By constructing a cohort of lung cancer patients, we demonstrated that the responses of GLI models under αPD1 treatment reflected the immunotherapy outcomes of the corresponding patients precisely. Furthermore, we dissected the various tumor immune processes mediated by PBMC-derived T cells within GLI models through functional multi-omics analyses, along with the characterization of circulating tumor-reactive T cells (GNLY+CD44+CD9+) with effector memory-like phenotypes as a potential indicator of immunotherapy efficacy. Our findings indicate that the GLI co-culture model can be used to develop diagnostic strategies for precision immunotherapies, as well as understanding the underlying mechanisms.

PMID:40513558 | DOI:10.1016/j.stem.2025.05.011

Improved tumor-type informed compared to tumor-informed mutation tracking for ctDNA detection and microscopic residual disease assessment in epithelial ovarian cancer

J Exp Clin Cancer Res. 2025 Jun 12;44(1):174. doi: 10.1186/s13046-025-03433-4.

ABSTRACT

BACKGROUND: Epithelial ovarian cancer (EOC) is a leading cause of cancer mortality in women, often diagnosed at advanced stages. While first-line treatments improve survival, relapses remain common, with 5-year survival rates below 40%. Circulating tumor DNA (ctDNA) is a promising biomarker for non-invasive EOC detection and monitoring. It may help assess treatment response, notably microscopic residual disease. Our objective was to compare two ctDNA characterization strategies in EOC for assessing tumor burden during first-line treatment: a tumor-informed approach based on somatic mutations and a tumor-type informed approach utilizing DNA methylation patterns.

METHODS: In the tumor-informed approach, whole exome sequencing (WES) was performed on EOC tumor DNA and matched PBMCs from 22 patients to identify tumor-specific mutations. Personalized panels were then designed to track these mutations in plasma cfDNA. In the tumor-type informed approach, differentially methylated loci (DMLs) were identified by comparing EOC samples, healthy ovarian tissues, and PBMCs. A unique custom methylation panel was designed, and a support vector machine classifier was trained to distinguish between methylation profiles in plasma cfDNA from healthy donors and from EOC patients. Plasma samples from 47 advanced-stage EOC patients receiving chemotherapy and 54 healthy subjects were analyzed.

RESULTS: For the tumor-informed approach, WES identified an average of 72 somatic mutations per patient. For the tumor-type informed approach, 52,173 DMLs were identified as tumor-specific markers. In 47 plasma samples tested by both approaches, ctDNA levels were significantly correlated (R = 0.56, p = 4.3 × 10-5), with 70.2% concordance in detection. At baseline, ctDNA was detected in 21/22 patients with the tumor-informed approach, and in 11/12 non-training baseline samples with the tumor-type-informed classifier. At end-of-treatment, the latter detected ctDNA in 16/22 samples, outperforming the former. Detection using this more sensitive approach was significantly associated with relapse (log-rank p = 0.009; hazard ratio = 9.44; 95% CI 1.22-73.26) and poorer overall survival (log-rank p = 0.041).

CONCLUSION: The tumor-type informed classifier demonstrated sensitivity and specificity for ctDNA detection, outperforming the tumor-informed approach in monitoring EOC progression. Requiring fewer sequencing data, it offers a practical, efficient solution for clinical management of EOC.

PMID:40506726 | PMC:PMC12160408 | DOI:10.1186/s13046-025-03433-4

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