• PARP inhibitors are among the most widely used therapies for ovarian cancer, but their long-term effectiveness is limited by acquired resistance 

• Researchers found a signaling pathway activated by the tumor microenvironment was a major driver of resistance, and blocking the pathway was able to resensitize tumors 

• The pathway was activated because the tumor microenvironment is acidic, which is common in several tumor types, demonstrating broad potential for this approach  

• Several drugs targeting this pathway already are in development, supporting potential future clinical investigation 

HOUSTON, JULY 29, 2026 ― Researchers at The University of Texas MD Anderson Cancer Center have discovered a promising strategy to overcome PARP inhibitor resistance in ovarian cancer, one of the most common barriers to the long-term effectiveness of this widely used treatment.  

Targeting a signaling pathway activated by the acidic tumor microenvironment restored sensitivity to PARP inhibitors in preclinical models, suggesting a potential new therapeutic strategy for overcoming acquired resistance. The study, published in Cancer Research, was led by Rugang Zhang, Ph.D., professor and chair of Experimental Therapeutics, and Kaixin Cheng, Ph.D., postdoctoral fellow in the Rugang Zhang Laboratory. 

“PARP inhibitors have transformed treatment for many patients with ovarian cancer, but resistance often limits their long-term effectiveness,” Zhang said. “This study revealed that the tumor microenvironment plays a critical role in driving treatment resistance and suggests a potential strategy for restoring sensitivity to PARP inhibitors and extending their benefit for patients.” 

How does an acidic microenvironment help tumors evade treatment? 

Acidity is a hallmark of many tumors, which often accumulate acid due to abnormal metabolism and poor blood flow. While tumor acidity has long been associated with resistance to cancer therapies, its effects on PARP inhibitor response remained unclear. 

PARP inhibitors block a key DNA repair pathway that cancer cells rely on for survival. These therapies are particularly effective in ovarian cancers that already have defects in DNA repair, such as tumors with BRCA mutations. However, many tumors eventually develop resistance to PARP inhibitors, leaving patients with fewer effective treatment options. 

In this study, researchers found that ovarian cancer cells exposed to acidic conditions became significantly less sensitive to PARP inhibitors. Acidic environments activated a signaling network involving ERK, p300 and PARP1 – proteins that collectively regulate cellular signaling, gene activity and DNA repair. Activation of this pathway reduced PARP trapping, a process in which PARP inhibitors lock PARP enzymes at sites of DNA damage to prevent repair. By reducing PARP trapping, this pathway decreases the effectiveness of these drugs. 

How does targeting this signaling pathway reverse treatment resistance? 

A large-scale CRISPR genetic screen identified p300 as a critical driver of the resistance pathway activated by tumor acidity. Researchers discovered that p300 adds a small chemical tag to PARP1 through a process called acetylation. This modification helped cancer cells avoid the DNA damage caused by PARP inhibitors.  

Disrupting this process with p300 inhibitors restored sensitivity to PARP inhibitors in ovarian cancer cells, leading to stronger antitumor responses across multiple preclinical models, including those with acquired PARP inhibitor resistance. 

The findings also suggest PARP1 acetylation and ERK activation may have potential as biomarkers of treatment resistance. Analysis of tumor samples from ovarian cancer patients treated with PARP inhibitors found that tumors with higher levels of activated ERK and acetylated PARP1 were more likely to be resistant to treatment and were associated with poorer outcomes.  

What’s next for this research? 

This study provides a strong rationale for further research on p300 inhibitors in ovarian cancer treatment. Future clinical trials could evaluate whether combining p300 inhibitors with PARP inhibitors could overcome treatment resistance or perhaps improve outcomes for patients who typically do not benefit from PARP inhibitors. 

Several p300 inhibitors, including IACS-16559, an agent developed by UT MD Anderson’s Therapeutics Discovery division, are being evaluated preclinically or are in early-stage clinical development, supporting the potential for further investigation of this therapeutic strategy. 

Additional research is needed to determine whether PARP1 acetylation and ERK activation could serve as biomarkers for predicting treatment response. Future studies also may identify additional mechanisms within the tumor microenvironment that drive treatment resistance, further expanding opportunities for therapeutic intervention. 

“One of the most striking findings was that the same amount of treatment was still reaching cancer cells, meaning the problem was not drug delivery,” Cheng said. “These findings suggest that the acidic tumor microenvironment may be an important therapeutic target alongside the cancer cell.” 

*** 

This research was supported by the National Institutes of Health, the U.S. Department of Defense, the Cancer Prevention and Research Institute of Texas (CPRIT), the Ovarian Cancer Research Alliance, and institutional support from UT MD Anderson and The Wistar Institute. For a full list of collaborating authors, disclosures and funding sources, see the full paper in Cancer Research.

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-26-0834

The team’s research, detailed in the Journal of Clinical Investigation, builds on prior observations that TNBC tumors are heterogeneous, exhibiting different cellular compositions that include diverse populations of tumor and immune cells. Among these immune cells, neutrophils and macrophages stand out as critical players. Dr. Xiang Zhang, the study’s senior author at Baylor College of Medicine, emphasized that variability in this immune cell landscape dictates the specific resistance mechanism a tumor might develop. Epithelial-like TNBC tumors, which harbor both macrophages and neutrophils, principally utilize neutrophil-driven pathways to evade chemotherapy, whereas mesenchymal-like tumors, dominated by macrophages, exploit these cells’ unique functional shifts to survive treatment.

Utilizing a robust experimental framework that combined investigations of human patient tissue samples with sophisticated mouse models, the researchers were able to dissect these resistance pathways with high resolution. Their previous research highlighted neutrophils as key facilitators in epithelial-like TNBC resistance, but the current study delves into mesenchymal-like tumors to examine macrophages’ role. Strikingly, macrophages in these tumors are not mere bystanders; chemotherapy itself appears to reprogram these immune cells, converting them from tumor-fighting sentinels into agents that actively suppress the immune response and assist tumor survival.

Dr. Liqun Yu, a co-first author of the study, elaborated that reprogrammed macrophages engage in a paradoxical behavior: while they continue to engulf and clear cancer cells, they simultaneously produce immune-suppressive molecules such as C1q and resolvin. These compounds inhibit cytotoxic immune cell activity, thereby creating an immunosuppressive microenvironment favorable for tumor cells to persist despite chemotherapy. This dual functionality of macrophages introduces a complex layer of resistance, highlighting the intricate crosstalk between cancer cells and the immune system within the tumor microenvironment.

To counteract this macrophage-mediated resistance, the research team explored several therapeutic strategies aimed at either eliminating macrophages or blocking their recruitment into mesenchymal-like tumors. Remarkably, these interventions restored sensitivity to chemotherapy, indicating that disabling the immunosuppressive capabilities of macrophages could reinvigorate the body’s natural defense mechanisms against tumor cells. Additionally, antagonizing the molecules secreted by the reprogrammed macrophages further revived the immune system’s antitumor response, underscoring new potential drug targets for overcoming resistance.

The implications of these findings extend beyond understanding resistance mechanisms; they usher in a new paradigm for personalized TNBC treatment. By profiling a tumor’s immune cell composition prior to therapy—discerning whether it aligns more closely with epithelial-like or mesenchymal-like characteristics—clinicians could predict the specific pathways the tumor might exploit to resist chemotherapy. This proactive approach could enable tailored treatment regimens that preempt resistance, employing immune modulatory agents alongside standard chemotherapy to block the tumor’s escape routes.

Furthermore, the delineation of discrete, mutually exclusive resistance mechanisms challenges the traditional one-size-fits-all model prevalent in oncological therapy. As noted by Dr. Zhang, the study reinforces that TNBC is not a monolithic entity; its heterogeneity demands nuanced therapeutic interventions. Targeting neutrophil-driven pathways in epithelial-like tumors while simultaneously addressing macrophage-mediated resistance in mesenchymal-like tumors could offer a dual-pronged strategy that enhances treatment efficacy across the TNBC spectrum.

The investigative team credits their progress to the integration of patient-derived samples for clinical relevance and genetically engineered mouse models that offer mechanistic insights. This translational research framework bridges laboratory findings with potential clinical applications, accelerating the pathway to novel therapies. Co-author Bo Wei from the University of Texas MD Anderson Cancer Center also contributed pivotal expertise, underscoring the collaborative, multi-institutional effort necessary to tackle the complexity of TNBC.

The study was supported through various grants from leading institutions including the National Institutes of Health, the Department of Defense, the National Cancer Institute, and the Breast Cancer Research Foundation. Such financial backing reflects the critical importance of continuing to unravel the cellular and molecular underpinnings of cancer resistance, which remains a substantial barrier to curing aggressive cancers like TNBC.

In summary, this groundbreaking research reveals that therapeutic resistance in TNBC emerges from distinct myeloid immune circuits shaped by the tumor’s cellular composition. The interplay of neutrophils and macrophages in crafting resistance pathways underscores the adaptive capabilities of the tumor microenvironment under therapeutic pressure. Targeting these circuits offers a tantalizing prospect for developing more effective, personalized therapies—potentially transforming the prognosis for patients afflicted by one of the most refractory breast cancer subtypes.

Subject of Research: Human tissue samples
Article Title: Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer
News Publication Date: 17-Feb-2026
Web References:

• Journal of Clinical Investigation
• Previous related study
  References: DOI 10.1172/JCI198815
  Keywords: Triple-negative breast cancer, TNBC, therapy resistance, macrophages, neutrophils, immunosuppression, tumor microenvironment, personalized medicine, chemotherapy resistance, immune modulation