Advancing Immunotherapy in Metastatic Cancers: Identifying Mechanisms, Targeting Sanctuaries

By: Jasenka Piljac Zegarac, PhD

From: ascopubs.org

Key Points:

• As the use of immunotherapy for the treatment of metastatic cancers advances, challenges remain in understanding the mechanisms of metastasis and why certain tumors spread to specific distant organs.
• Oncologists still treat metastatic disease based on the original tumor site, and most treatment guidelines often do not consider the specific site of metastasis in treatment selection.
• Understanding the mechanisms of metastasis can potentially help researchers identify key vulnerabilities that can be targeted by future immunotherapies.

Over the past decade, the field of oncology has made significant strides in the use of immunotherapy for the treatment of metastatic cancers; however, challenges remain in understanding the mechanisms of metastasis to specific organs, as well as in targeting the specific sites of metastasis. In a June 1 Education Session at the 2026 ASCO Annual Meeting, “Breaking Immune Sanctuary: Targeting Metastatic Niches,” 3 experts will discuss the latest advancements and challenges in this complex area of cancer care.

Current Immunotherapy Approaches to Metastasis

The session will be chaired by Raghav Sundar, MD, PhD, of Yale School of Medicine, with presentations delivered by Emilie Le Rhun, MD, PhD, of the University Hospital Zürich, Switzerland, and Brian J. Czerniecki, MD, PhD, of Moffitt Cancer Center. The topics covered include the mechanisms of metastasis in solid tumors, approaches to targeting the various sites of metastases, and ways in which modulation of the tumor microenvironment can improve responses to immunotherapy.

Dr. Sundar explained that the goal of the session is to discuss the latest insights on the mechanisms of metastasis and organotropism―why certain tumors spread to specific distant organs. Although over the past decade novel immunotherapies have improved survival outcomes in patients with metastatic cancers, oncologists still treat metastatic disease based on the original tumor site, and most treatment guidelines often do not consider the specific site of metastasis in treatment selection. “However, the current immunotherapy approaches frequently do not work as well in specific sites of metastasis. For example, we know that immunotherapy may not work as well in peritoneal, brain, or bone metastases but may work well in patients with lung metastases,” he said. “Moreover, the way liver metastases respond to immunotherapy is very different. We are going to talk about some of the newer ways in which we are trying to approach these immune sanctuaries and the finding that the microenvironments of these metastatic sites are likely to be different from the microenvironment of the primary tumor.”

Mechanisms of Metastasis

Dr. Sundar’s lecture, “Foundations of Premetastatic Niche Formation,” will be divided into 3 parts. “In the first part, I will discuss the specific characteristics that primary tumors tend to acquire to travel to a metastatic site,” he said. “We also have a lot of emerging data that show that metastatic sites also start to transform in a way that they can receive tumor cells spreading towards them, which is what we call a premetastatic niche.” Dr. Sundar is optimistic that understanding these mechanisms can help researchers identify the key vulnerabilities that can be targeted by future immunotherapies.

In the second part of his lecture, Dr. Sundar will discuss the different mechanisms tumors use to get to specific metastatic sites (the principle of organotropism). “Finally, I will talk about the current technology and tools available to study these metastatic niches and the microenvironment . . . for example, single-cell sequencing and spatial profiling, and going beyond bulk DNA and RNA sequencing, which is what is currently used in the clinic.”

Metastatic Sanctuaries and the Tumor Microenvironment

In her presentation entitled “Targeting Metastatic Sanctuaries,” Dr. Le Rhun will talk about ways to target specific metastatic sanctuaries, specifically brain metastases. She will also discuss intrathecal delivery of therapeutics.

In the final presentation of the Education Session, entitled “Intratumoral Immunotherapy and Local Immune Activation,” Dr. Czerniecki will discuss the approach of activating the tumor microenvironment with local therapies to achieve systemic effects. His expertise is in the area of breast cancer and approaches to targeting the tumor microenvironment in breast cancer.

Dr. Sundar hopes that this Education Session will bring to light novel insights valuable to all oncologists. “[Attendees] will learn about the ways in which we are developing immunotherapeutic approaches to treating cancer, and, particularly, in targeting the specific sites of metastasis and the microenvironment,” he said.