Innovative Cancer Immunotherapy Approaches

Stanford scientists have discovered that cancer cells don’t just use one trick to hide from the immune system—they use two separate “don’t-eat-me” signals to stop macrophages from killing them. The first signal, CD47, was already famous for acting like an invisibility cloak that tells macrophages to back off, and blocking it with an anti-CD47 antibody is already in human trials. In the Nature Immunology paper, the same Stanford team also found that tumors use MHC class I as a second stop signal by binding to a macrophage receptor called LILRB1, which suppresses the macrophage’s ability to engulf and destroy the cancer. When researchers blocked both CD47 and LILRB1 in mice, tumors rapidly filled with immune cells, shrank significantly, and became far easier for the body to clear. This shows that many cancers survive by running two overlapping escape systems, and turning off both “don’t-eat-me” pathways at once may dramatically boost the immune system’s ability to attack and eliminate tumors.

Published today in Nature, Camilo Faust Akl et al. (Keith Ligon, Nino Chiocca, Francisco Javier Quintana) reveal that GBM co-opts TRAIL+ astrocytes to suppress anti-tumor immunity. The team identify a distinct subset of TRAIL+ astrocytes within the GBM tumor microenvironment that induces apoptosis in CD4⁺ and CD8⁺ T cells via a GBM-secreted IL-11 -> STAT3 signaling axis. These astrocytes also modulate microglia- and monocyte-derived TAMs, further amplifying T cell dysfunction. Notably, high TRAIL and IL-11 expression correlated with faster recurrence and worse survival in GBM patients, underscoring the clinical relevance of this pathway. Crucially, this immunosuppressive circuit can be therapeutically disrupted using an oHSV engineered to express an anti-TRAIL scFv—providing a compelling proof-of-concept for precision immunovirotherapy in GBM. Mass General Brigham, Harvard Medical School, Baylor College of Medicine, Boston University School of Medicine, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, The University of Freiburg, McGill University

Gut bacterium may be helping breast tumors hide from the immune system. And it appears to do it through a metabolite. Researchers found that Enterocloster bolteae, a member of the Lachnospiraceae family, became progressively more abundant as breast tumors developed. Its rise was linked to higher levels of deoxycholic acid, a secondary bile acid produced through microbial metabolism. But the metabolite did not remain confined to the gut. Deoxycholic acid accumulated inside the tumors and activated the farnesoid X receptor, or FXR, in cancer cells. That activation triggered NF-κB signaling and increased production of interleukin-6. IL-6 then recruited immune cells that can suppress antitumor immunity, including granulocytic myeloid-derived suppressor cells and T helper 17 cells. The result was a tumor microenvironment that appeared more capable of protecting the cancer from immune attack. The pathway looked like this: Enterocloster bolteae → deoxycholic acid → tumor FXR activation → NF-κB signaling → IL-6 production → immunosuppressive immune-cell recruitment → breast cancer progression This is more than another study showing that cancer is “associated” with changes in the microbiome. It proposes a specific biological chain connecting a gut organism, a circulating microbial metabolite, a receptor inside the tumor and a measurable immune response. Even more importantly, blocking FXR or IL-6 signaling weakened these effects in the experimental models. That creates several potential intervention points. Not just the bacterium itself, but its metabolic output, the tumor receptor it activates and the downstream inflammatory signal. This does not mean that modifying the microbiome can currently prevent or treat breast cancer. But it strengthens a much bigger idea: The gut microbiome may influence cancer progression from a distance by producing molecules that reach the tumor and reshape its immune environment. The next generation of cancer therapeutics may not focus only on the tumor. It may also target the microbial chemistry helping the tumor survive.

After reviewing the recent Nature Communications paper alongside relevant AACR25 abstracts, I’ve identified several key insights into the mechanisms driving the efficacy of trastuzumab deruxtecan (T-DXd): The antibody component in ADCs plays a broader role than target recognition. T-DXd retains FcγR binding and induces ADCP, showing that Fc-effector functions can independently promote anti-tumor immunity. Thus, when designing ADCs, the immune-activating properties of the antibody may be considered where appropriate, particularly in settings where immune mechanisms contribute meaningfully to therapeutic effects. In tumors with low antigen expression, the bystander effect alone cannot account for T-DXd’s efficacy. This study shows that T-DXd is active in HER2-low and HER2-ultralow breast cancers without HER2 binding or internalization. Instead, extracellular cleavage of the linker by Cathepsin L (CTSL) in the tumor microenvironment enables payload release. The bystander effect, by contrast, requires HER2-high cells and is less relevant in these contexts. These findings challenge the internalization-centric paradigm of ADCs. Extracellular payload release—mediated by proteases like CTSL—may be more relevant in certain tumors. CTSL’s broad expression in invasive breast cancer may serve as a biomarker or selection criterion for cleavable-linker ADCs. The DXd payload induces potent immunogenic cell death (ICD), marked by extracellular ATP, HMGB1 release, and calreticulin exposure—activating myeloid cells and enhancing ADCP and antigen presentation via TLR4 and STING/IFN-I pathways. While the study demonstrates DXd activates the STING/IFN-I pathway, upstream events like cytosolic dsDNA release or cGAS activation were not directly assessed. Thus, the “dsDNA → cGAS–STING” mechanism remains a hypothesis based on indirect evidence, warranting further investigation. Still, it supports combination strategies leveraging the immunomodulatory properties of topo I-based payloads like DXd. Interestingly, while DXd upregulates “eat-me” signals such as calreticulin, it also elevates CD47 expression—a “don’t eat me” signal. This duality suggests that combining T-DXd with CD47 blockade could further enhance innate immune responses. The study confirms that anti-CD47 therapy increases ADCP, CD8+ T cell infiltration, and long-term immune memory, supporting rational combinations of T-DXd or Dato-DXd with agents like DS-1103. Ultimately, ADC efficacy is shaped not just by antigen expression but by the mechanism of payload release, Fc-effector retention, ICD induction, and the immune contexture of the TME. Future patient stratification strategies should consider antigen levels, protease activity, immune composition, and inflammatory signaling. https://lnkd.in/gz9gAnBF

Recently, a study published in Nature Immunology caught my eye. In it, the authors undertook an extensive study that charts generic variations influencing the tumour microenvironment (TME). The TME plays a crucial role in tumour progression and response to treatment. Understanding the genetic underpinnings of the TME could help pave the way for novel therapeutic approaches and enhanced treatment targeting. One of the study's most interesting aspects is its use of machine learning methods and advanced bioinformatic approaches to analyze and integrate large-scale datasets. The advanced computational methods used enabled identification of genetic variations that may have otherwise been overlooked, highlighting the power of computational biology in advancing our understanding of cancer. Leveraging these techniques, the researchers created a detailed atlas of genetic factors impacting the TME, which they refer to as immunity quantitative trait loci (immunQTLs), and showed that many of these genetic factors were likely co-localized with previously known expression quantitative trait loci. This observation suggests that the immunQTLs may contribute to the cellular heterogeneity observed within the TME by influencing the expression of genes modulating immune infiltration. Going beyond their initial discovery-driven computational work to further validate their findings, they mapped immunQTLs across >1,600 genes and 23 cancers that are associated with cancer pathogenesis and immune regulation. Diving even deeper, they went on to experimentally validate that one of the identified genes, CCL2, which is implicated in promoting colorectal carcinoma (CRC) progression by allowing tumour cells to evade immunity, may be a promising therapeutic target. This finding demonstrates the potential of the depth of the data set and how it might be used to identify and validate targets. This publication presents a significant amount of work that I have only scratched the surface of here. It offers new insights into the complexity of genetic factors influencing the TME, providing a comprehensive genetic map of the TME and its implications for cancer therapy. The authors have made their data available through a publicly accessible database to help propel further work by the research community. To me, an exciting aspect of this work is that it may help open the door to future combination therapeutic approaches that target both the tumour cells and their microenvironment. https://lnkd.in/ezRckvFh

𝗖𝗼𝘂𝗹𝗱 𝘁𝗵𝗶𝘀 𝗯𝗿𝗲𝗮𝗸𝘁𝗵𝗿𝗼𝘂𝗴𝗵 𝘁𝗲𝗰𝗵𝗻𝗼𝗹𝗼𝗴𝘆 𝗯𝗲 𝘁𝗵𝗲 𝗻𝗲𝘅𝘁 𝗳𝗿𝗼𝗻𝘁𝗶𝗲𝗿 𝗶𝗻 𝗰𝗮𝗻𝗰𝗲𝗿 𝘁𝗿𝗲𝗮𝘁𝗺𝗲𝗻𝘁? Exciting news from the Korea Advanced Institute of Science and Technology research team led by Professor Kwang-Hyun Cho has developed a groundbreaking method to transform colon cancer cells back into normal-like cells without destroying them. This innovative approach, termed “reversible cancer treatment technology,” could potentially eliminate the side effects commonly associated with traditional cancer therapies. Traditional cancer treatments often aim to kill cancer cells, which can lead to resistance and adverse effects on normal cells. Professor Cho’s team observed that cancer cells follow a reverse trajectory of normal cell differentiation when becoming cancerous. By developing a digital twin of the gene network involved in normal cell differentiation, they identified key molecular switches that guide this process. Applying these switches to colon cancer cells successfully reverted them to a normal-like state, as confirmed through molecular and cellular experiments, as well as animal studies. This breakthrough highlights the importance of continued investment in scientific innovation and offers hope for more targeted and less invasive cancer treatments in the future. #CancerResearch #Biotechnology #MedicalInnovation #Healthcare #ScientificBreakthrough #Korean #Innovative

Can we combine CAR-T cell therapy with bispecific T-cell engager antibodies? A remarkable study published by researchers at the Vall d’Hebron Institute of Oncology (VHIO) in Barcelona shows the synergistic combination of two separate mechanisms to fight solid tumors: CAR-T cell therapy and secretion of a bispecific antibody.  This novel concept for CAR T-cell therapy demonstrates efficacy and safety in preclinical models of HER2-positive solid tumors and possibly combines the best features of both quite powerful modalities to achieve clinical success for hard to treat tumors.  The scientists have generated CAR-T cells targeting p95HER2 and engineered them to secrete a bispecific HER2 x CD3 antibody (TECH2Me). Both therapies specifically and independently recognize tumor cells. In addition, the TECH2Me bispecific antibody activates immune cells within the tumor microenvironment. This dual mechanism of action has demonstrated safety and achieved complete and durable antitumor responses in patient-derived models of HER2+ p95HER2-expressing solid tumors. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors. Original publication: https://lnkd.in/e-VNqm5U Further reading: https://lnkd.in/eBB7S3KE https://lnkd.in/eYa5aQEK https://lnkd.in/eMX77Far https://lnkd.in/ehH9dUuK https://lnkd.in/eXCqnzJt https://lnkd.in/e7CpDvuq

Scientists at the Icahn School of Medicine at Mount Sinai have reported a striking new #immunotherapy approach that challenges how we think about treating metastatic solid #cancers. Rather than targeting cancer cells directly, the team focused on dismantling the #tumor’s immune shield, namely the supportive cells that protect cancer from immune attack. ▫️ Published in Cancer Cell, the study tested this strategy in aggressive preclinical models of metastatic #lungcancer and #ovariancancer, two diseases that have historically been resistant to existing immunotherapies. The key obstacle, the researchers note, is the tumor microenvironment, a highly immunosuppressive “fortress” built largely by tumor-associated macrophages. ▫️Led by Jaime Mateus-Tique, PhD and senior author Brian Brown, PhD, the team engineered #CARTcells to target these tumor macrophages instead of cancer cells themselves. Crucially, the CAR-T cells were further armored to locally release interleukin-12 (IL-12), a potent immune-activating cytokine. ▫️The result was elimination or reprogramming of tumor macrophages, reversal of immune suppression, and recruitment of endogenous killer T cells into the tumor. In mouse models, this led to durable tumor control, prolonged survival, and complete cures in many cases. Advanced spatial genomics confirmed a fundamental reshaping of the tumor microenvironment from immune-silent to immune-active. ▫️The authors emphasize that this is proof of concept rather than a clinical cure, and that human studies are needed to establish safety and efficacy. Ongoing work is focused on refining control of IL-12 delivery to maximize benefit while minimizing toxicity. 💡 This work opens a new path for CAR-T therapies by dismantling the defenses that allow tumors to survive. 🗃️ See comments section for reference

Cleveland Clinic researchers have discovered that bacteria inside cancerous tumors may be key to understanding why immunotherapy works for some patients but not others. Two new studies, published simultaneously in Nature Cancer, reveal that elevated levels of bacteria in the tumor microenvironment suppress immune response, driving resistance to immunotherapy in patients with head and neck squamous cell carcinoma. In the second paper, a data analysis of the Javelin HN100 Phase III clinical trial tested whether adding anti-PDL1 immunotherapy to standard chemoradiotherapy improved outcomes for patients with head and neck squamous cell carcinoma. The analysis confirmed that patients with high tumor bacteria levels had poorer outcomes with immunotherapy compared to standard chemoradiotherapy. Together, the two studies showed that elevated bacteria levels in tumors attract neutrophils, white blood cells that fight infection. While neutrophils are essential for combating bacterial infections, in cancer they can suppress the immune system needed for immunotherapy to work effectively. These findings lay the foundation for future research on why bacteria are attracted to tumors and how to modify them to improve treatment. Source in comments.

Despite advances in cell therapies, solid tumors remain hard to treat. The tumour microenvironment prevents immune cells from getting in. Scientists used CRISPR to make tumors “immune welcoming”. CAR-T cells work really well for blood cancers. Not so much for solid tumors. The tumor microenvironment (TME) actively blocks immune cells from getting in. The result? T cells are pushed away and immune responses suppressed. But what if we flipped the switch and made TMEs attractive? CRISPR is used for gene therapies. Why not use it to engineer tumor cells to secret immune-attracting signals? TMEs would go from hostile to welcoming. For this to work, we need tumor-specific integration sites. Finding these sites manually across thousands of mutations is like looking for a needle in a haystack. We need an automated way to identify the best, safest targets for each patient. That’s exactly what these scientists did. How did they do it? → Built CancerPAM, a bioinformatics pipeline that analyzes tumor sequencing data to find tumor-specific mutations. These mutations act as CRISPR target sites (PAM sequences) → Ranked these sites according to safety and efficiency → Tested CRISPR knock-in of cytokine genes (CXCL10, CXCL11, IFNG) in neuroblastoma cell lines → Confirmed site-specific integration using dPCR and flow cytometry → Tested efficacy in xenograft mouse models and humanized mice The results? Pretty outstanding. → CancerPAM identified a median of 130 tumor-specific CRISPR sites per neuroblastoma patient with 99% accuracy → Successfully integrated the 3 cytokine genes with stable expression → 2-3x times higher CAR-T cell infiltration in 3D tumors models secreting CXCL10 or CXCL11 → 132% to 221% higher early CAR-T infiltration in xenograft mice with CXCL10-expressing tumors → 88% tumor control in CXCL10-expressing tumors vs 29% in controls in humanized mice → Event-free survival more than doubled (49 vs 21 days) CRISPR can be used to reprogram tumors to become immune-friendly and CancerPAM makes personalized therapy possible. Tumor heterogeneity means that each patient presents different mutations. In this study, integration site recurrence was very low (1.4-5.6%), meaning each patient would need a custom target. This makes manufacturing challenging, but also highlights the need for this kind of individualized approach: CancerPAM can do the grunt work and identify safe integration sites specific to each patient relatively quickly. It’s a paradigm switch. Rather than forcing CAR-T cells into hostile TMEs, or systematically dosing patients with cytokines, you can turn the tumor into a cytokine-making factory. What do you think of this approach?