This Week in Oncology — Jun 25, 2026

Welcome to This Week in Oncology. This week we're covering 8 notable papers spanning long-term outcomes in cellular immunotherapy, novel strategies to overcome resistance in solid tumors, and the biological drivers of early-onset cancer. Let's dive in.

Let's begin with cellular immunotherapy and the immune microenvironment, where we are seeing both extraordinary long-term data and innovative platforms for the future. In the New England Journal of Medicine, researchers published a landmark study evaluating ten-year outcomes of patients treated with anti-CD19 chimeric antigen receptor T-cell therapy, specifically tisagenlecleucel, for relapsed or refractory B-cell non-Hodgkin lymphomas [1]. This analysis followed 38 heavily pretreated patients, including 24 with large B-cell lymphoma and 14 with follicular lymphoma, for a median of 10.1 years, ranging from 7.9 to 11.5 years. Remarkably, the investigators found that no relapses occurred beyond 5.4 years, suggesting a potential curative profile for a subset of patients. At ten years, the lymphoma-free survival was 32% for those with large B-cell lymphoma and 47% for those with follicular lymphoma. When accounting for deaths from any cause, the ten-year progression-free survival was 17% in the large B-cell cohort and 29% in the follicular lymphoma group, while the ten-year overall survival was 17% and 50%, respectively. While these long-term remissions are highly encouraging, the study also highlights the ongoing need for vigilance, as a second primary cancer developed in 9 patients, representing a ten-year cumulative incidence of 21%, and ten-year non-relapse mortality was 18%. Persistent grade 2 or 3 neutropenia occurred in 5% of patients, and B-cell aplasia persisted in 44% of those with a long-term response. This long-term perspective is vital for counseling patients on the late risks and true curative potential of CAR T-cell therapy.

To build on the success of cellular therapies, researchers are looking beyond traditional T cells. Writing in Cell, investigators have developed a novel cellular immunotherapy platform using expanded and engineered granulocyte-monocyte progenitors, or GMPs [6]. While macrophages are highly attractive for tumor immunotherapy, their clinical translation has been severely hindered by poor ex vivo expansion and genetic tractability. By identifying myeloperoxidase as a key regulator of GMP proliferation, this team established culture conditions that permit long-term expansion of both mouse and human GMPs without losing their progenitor identity or myeloid potential. Once transferred, these expanded GMPs successfully home to hematopoietic niches and generate donor-derived myeloid cells, including abundant tumor-infiltrating macrophages. When engineered with chimeric antigen receptors, these GMPs successfully suppressed CD19-positive leukemia and human epidermal growth factor receptor 2-positive solid tumors in preclinical models. Furthermore, by incorporating a chimeric receptor with an immunoglobulin G Fc domain, the researchers were able to recruit host phagocytes and prime T cells across major histocompatibility complex mismatches, offering a scalable, off-the-shelf alternative for solid tumor immunotherapy.

At the same time, our understanding of how the immune system destroys tumors is expanding beyond direct cytotoxic killing. A study published in Science reveals that tumor antigen-specific CD4 positive T cells can impair tumor growth through a stroma-targeting mechanism that depends on myeloid cells and tumor necrosis factor-mediated vascular damage [8]. Using multiplex immunofluorescence and single-cell and tissue transcriptomics, the authors demonstrated that CD4 positive T cells trigger the formation of perivascular myeloid cell clusters. These clusters contain classically activated macrophages that produce tumor necrosis factor in response to T-cell-derived interleukin-3. This localized burst of tumor necrosis factor causes severe intratumoral endothelial damage and blood supply disruption, resulting in localized tumor cell death. Crucially, this means that intratumoral antigen-triggered T-cell activation can exert profound antitumor effects without requiring direct recognition of living tumor cells, offering a promising way to bypass many of the antigen-loss and escape mechanisms that typically limit anti-tumor immunity.

Next, we turn to solid tumors, where several new studies address the persistent challenge of therapeutic resistance, focusing on antibody-drug conjugates, targeted small molecules, and immunotherapies. In the Annals of Oncology, researchers reported results from the SACI-IO HR-positive randomized phase two trial, which evaluated whether adding the programmed death-1 inhibitor pembrolizumab to the antibody-drug conjugate sacituzumab govitecan improves outcomes in patients with metastatic hormone receptor-positive, HER2-negative breast cancer [5]. Sacituzumab govitecan is already an approved topoisomerase one inhibitor-based conjugate for this population, but preclinical data suggested immunotherapy might synergize with it. In this trial of 104 patients enrolled between March 2021 and January 2024, the addition of pembrolizumab to sacituzumab govitecan did not significantly improve progression-free survival in the overall population, with a median of 8.4 months in the combination arm versus 6.7 months with the conjugate alone. Overall survival was also similar, at 20.0 months versus 18.0 months, respectively, and the objective response rate was 28.8% versus 19.2%. However, in the 44% of patients who were PD-L1-positive, there was a notable numerical trend favoring the combination, with a median progression-free survival of 11.1 months compared to 5.6 months with sacituzumab govitecan alone, and a median overall survival of 18.5 months versus 12.5 months. While this did not reach statistical significance in this phase two cohort, it suggests that PD-L1 selection may be crucial for future combination trials. Correlative analyses also revealed that higher circulating tumor DNA fraction and PIK3CA mutations were associated with worse progression-free survival, while plasma epigenome-pathway analysis suggested that high cell-cycle or epithelial-to-mesenchymal transition activation may confer sensitivity or resistance to sacituzumab govitecan, respectively.

The therapeutic potential of targeting TROP2 is also being leveraged in lung cancer to delay resistance to epidermal growth factor receptor tyrosine kinase inhibitors. In Cancer Cell, a study identified TROP2 as a dynamically upregulated target during the formation of drug-tolerant persister cells, which are a major driver of eventual resistance to osimertinib in EGFR-mutant non-small-cell lung cancer [7]. Mechanistically, the researchers discovered that c-Myc acts as a transcriptional repressor of TROP2. When osimertinib or other tyrosine kinase inhibitors block the MAPK pathway, c-Myc levels drop, which directly upregulates TROP2 expression on these surviving persister cells. By combining the TROP2-targeting antibody-drug conjugate sacituzumab tirumotecan with osimertinib, the investigators were able to eliminate these drug-tolerant persisters and significantly delay tumor relapse in preclinical models. An ongoing phase two trial of this combination in the first-line setting is already showing highly encouraging preliminary efficacy, pointing to a potential new standard of care to prevent or delay resistance.

In another effort to address resistance in non-small-cell lung cancer, a study in Cancer Discovery characterized the unique properties and vulnerabilities of KRAS codon 13 mutations, which have been less understood than the common codon 12 mutations [4]. By analyzing a large multi-national cohort and preclinical models, the authors found that KRAS G13C and G13D mutations actually confer reduced oncopotency compared to their codon 12 counterparts, and are frequently associated with specific co-mutations such as KEAP1, STK11, BRAF, and NF1. Using a novel active-state selective KRAS G13C inhibitor, RMC-8839, the researchers demonstrated reduced viability in KRAS G13C lung cancer models. Furthermore, a drug repurposing screen revealed that these models are selectively vulnerable to chemotherapy. Combining RMC-8839 with docetaxel produced robust, synergistic anti-proliferative activity both in vitro and in vivo, highlighting a promising direct combination strategy for this distinct molecular subset.

To round out our discussion on overcoming resistance, a paper in Cell explores a fascinating intersection between immunotherapy and cuproptosis, a newly identified form of copper-dependent cell death [3]. The study reveals a reciprocal crosstalk where CD8 positive T cell-mediated antitumor immunity enhances the susceptibility of tumor cells to cuproptosis. Mechanistically, cuproptotic tumor cells undergo immunogenic cell death, releasing damage-associated molecular patterns that activate dendritic cells and boost T-cell responses. In turn, CD8 positive T cell-derived interferon-gamma upregulates the key cuproptosis regulator FDX1 via the STAT1-IRF1 signaling axis, making the tumor cells highly sensitive to copper-induced death. Combining a cuproptosis inducer with anti-PD-L1 therapy successfully amplified tumor clearance and overcame PD-L1 resistance across multiple preclinical models, suggesting that exploiting this metabolic-immune loop could rejuvenate immunotherapy responses in resistant tumors.

Finally, we look at a critical epidemiological trend published in Nature Medicine, which investigates the alarming global rise of early-onset cancers in younger generations [2]. To understand the underlying drivers, researchers analyzed data from over 154,000 young adults in the United Kingdom Biobank, measuring systemic biological aging using the PhenoAge algorithm. They observed a clear generational shift, with biological aging increasing across successive birth cohorts; specifically, there was a 23% standard deviation increase in biological age for individuals born between 1965 and 1974 compared to those born between 1950 and 1954. This accelerated biological aging was directly associated with an increased risk of early-onset solid cancers, particularly lung, gastrointestinal, and uterine cancers, independent of genetic risk. Organ-specific proteomics further linked immune system aging to early-onset lung cancer and adipose tissue aging to early-onset colorectal cancer. These findings, which were partially validated in over 10,000 participants from the United States All of Us Research Program, suggest that advanced biological aging relative to chronological age is a major driver of early-onset cancers, pointing to the urgent need for early screening and preventative strategies targeting biological aging.

If you only have time for one paper this week, make it the ten-year follow-up of CAR T-cell therapy for B-cell lymphomas published in the New England Journal of Medicine [1]. This study provides the longest clinical follow-up data to date for tisagenlecleucel, confirming that a single infusion can lead to decade-long, potentially curative remissions in a substantial proportion of patients, while also providing crucial data on long-term safety and second primary malignancies.

Here are the key takeaways from this week in Oncology:

First, anti-CD19 CAR T-cell therapy can induce decade-long remissions in relapsed or refractory B-cell lymphomas, with no relapses observed beyond five point four years, though long-term monitoring for second primary cancers and late cytopenias remains essential.

Second, adding pembrolizumab to sacituzumab govitecan does not significantly improve outcomes for unselected metastatic hormone receptor-positive, HER2-negative breast cancer, but a strong numerical trend in PD-L1-positive patients suggests this subgroup warrants further dedicated clinical trials.

Third, combining the TROP2-targeting antibody-drug conjugate sacituzumab tirumotecan with osimertinib represents a promising strategy to eliminate drug-tolerant persister cells and delay resistance in epidermal growth factor receptor-mutant non-small-cell lung cancer.

Fourth, accelerated biological aging, independent of genetic risk, is rising across recent generations and is strongly linked to the risk of early-onset solid tumors, particularly lung, gastrointestinal, and uterine cancers.

And fifth, novel therapeutic platforms, such as engineered granulocyte-monocyte progenitors and cuproptosis-inducing combinations, are showing massive potential in preclinical models to overcome traditional barriers to immunotherapy.

That's your roundup for This Week in Oncology. The full transcript and references are available on the episode page in your AudioScholar library. This is an AI-curated summary — for clinical decisions, always consult primary sources and current guidelines. See you next week.

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This is an automated summary generated by artificial intelligence, which can make mistakes. Always review the original source materials.