# Beyond Resection: Surgery as an Evolutionary Bottleneck Shaping Tumor Evolution and Treatment Response in Diffuse Gliomas

## TL;DR

This paper explores how surgery affects tumor evolution in brain tumors, suggesting it shapes the tumor environment and influences treatment response.

## Contribution

The paper introduces the concept of surgery as an evolutionary bottleneck influencing tumor recurrence and treatment outcomes in diffuse gliomas.

## Key findings

- Surgical trauma induces inflammation, hypoxia, and immune changes that reshape the tumor microenvironment.
- Surgery creates selective pressures favoring adaptive tumor cell populations and influencing recurrence patterns.
- The paper highlights the dissociation between anatomical and molecular surgical margins, explaining distant recurrences.

## Abstract

Surgery is a cornerstone in the treatment of central nervous system tumors, especially diffuse gliomas. Traditionally, its value has been measured mainly by how much tumor can be removed. However, most malignant CNS tumors recur even after apparently complete resections, indicating that surgery affects more than tumor volume. In this review, we discuss how surgical injury can reshape the tumor microenvironment by inducing inflammation, hypoxia, vascular and extracellular matrix remodeling, and immune changes. These postoperative conditions may favor adaptive tumor cell populations and influence where and how tumors recur, as well as how they respond to radiotherapy and systemic treatments. We propose that surgery should be considered a biological inflection point that contributes to tumor evolution. Recognizing this may help refine postoperative risk stratification and support more personalized, biology-informed adjuvant strategies.

Surgical resection remains a cornerstone in the multidisciplinary management of central nervous system (CNS) tumors, particularly diffuse gliomas. Traditionally, the role of surgery has been evaluated primarily through quantitative metrics such as extent of resection and its association with survival outcomes. However, despite maximal and radiologically complete resections, recurrence remains nearly universal in malignant CNS tumors, suggesting that surgical cytoreduction alone does not fully account for post-surgical disease dynamics. Emerging biological and molecular evidence indicates that surgery represents not merely a technical intervention, but a biologically active event that profoundly reshapes tumor evolution and treatment response. In this review, we propose a conceptual framework that redefines surgery as a key biological driver in CNS tumor progression. We synthesize evidence demonstrating that surgical trauma induces inflammation, hypoxia, vascular remodeling, immune modulation, and extracellular matrix reorganization, collectively reprogramming the residual tumor microenvironment. These changes create selective pressures that favor the survival and expansion of adaptive tumor cell subpopulations, including invasive and stem-like phenotypes. From an evolutionary perspective, surgical resection functions as an acute selective bottleneck acting on heterogeneous tumor ecosystems, contributing to clonal selection and molecular divergence at recurrence. We further examine the dissociation between surgical (anatomical) margins and molecular (biological) margins, highlighting how biologically active tumor cells infiltrate beyond radiologically defined boundaries. This discrepancy provides a biological explanation for marginal and distant recurrences and challenges anatomy-based paradigms of surgical completeness. Importantly, we discuss how surgery-induced biological changes influence postoperative radiotherapy and systemic therapies, affecting radiosensitivity, target delineation, and therapeutic vulnerability. Finally, we outline future directions toward surgery-integrated precision neuro-oncology, emphasizing the potential of spatial profiling, liquid biopsy, advanced imaging, and artificial intelligence to capture perioperative tumor evolution. By reframing surgery as a biological inflection point rather than a neutral prelude to adjuvant treatment, this review advocates for a dynamic, biology-driven continuum of care aimed at anticipating tumor adaptation and improving long-term disease control in CNS tumors.