Introduction
For our Spring Newsletter (for full newsletter, see link below) I have been reflecting on immunotherapy and its relation to palliative care. The recent remarkable advances in cancer immunotherapy are now widely recognized not only among healthcare professionals but also by the general public. The field of palliative care for cancer has also entered an era in which its relationship with cancer immunotherapy is being actively explored. In the past, I was involved in research on tumor immunity [1], and I have continued to study tumor immunity through the Department of Pathology at my alma mater, Sapporo Medical University [2]. In this article, I will provide an overview of recent developments in cancer palliative care and tumor immunity based on my experiences.The Philosophy of Palliative Care and Tumor Immunity
Palliative care is a practice that addresses the human experiences of birth, aging, illness, and death (the four sufferings in Buddhist philosophy) and seeks to safeguard ‘human dignity’. I believe that the philosophy of palliative care aligns closely with that of the immune system.
The immune system functions as a biological defense mechanism that eliminates non-self-elements. However, cancer cells exploit immunosuppressive mechanisms to proliferate, evade immune surveillance, and assimilate and proliferate into the body as if they were part of the self. Even when cancer immunotherapy proves effective, the immune system accompanies the process throughout the entire journey (the process of birth, aging, illness, and death) and, in doing so, safeguards ‘human dignity’.Remarkable Advancements in Cancer Immunotherapy
Historically, although targeting many diseases, hospice and palliative care developed with a focus on cancer. This is largely because cancer, with its association with “pain,” has been one of the most symbolic, psychologically and physically burdensome illnesses for humans. As previously mentioned, palliative care for cancer has recently entered a new era that places greater emphasis on biology [3].
Within the field of oncology, which underpins this shift, the progress of tumor immunology has been particularly remarkable. Cancer immunotherapy has led to the emergence of long-term survivors (some even appearing to be completely cured) despite being diagnosed with stage IV cancer. The 2016 paper by Samuel J. Harris, titled “Raising the Tail of the Kaplan-Meier Survival Curve” [4], is widely known in this context. The turning point was the introduction of the first immune checkpoint inhibitor, nivolumab, in 2014.
This was followed by the approval of the CAR-T (Chimeric Antigen Receptor T-cell) therapy drug tisagenlecleucel in 2017 and, most recently, the launch of the TCR-T (T-cell Receptor T-cell) therapy drug afamitresgene autoleucel in 2024. These breakthroughs have made cancer immunotherapy one of the most remarkable developments in recent years.
However, the effectiveness of immune checkpoint inhibitors (ICIs) remains limited. Moreover, immune-related adverse effects (irAEs) pose significant concerns, particularly those involving serious autoimmune reactions. The research on and clinical applications of CAR-T and TCR-T cell therapies, thus, remain in their early stages.The Current State of Tumor Immunology
Tumor immunology has undergone rapid development, evolving from foundational studies on immune responses to clinical applications. One widely recognized conceptual framework is the cancer-immunity cycle [5], an illustrative model that explains anti-tumor immune responses by tumor-specific T cells in seven steps: 1) Release of cancer cell antigens, 2) Cancer antigen presentation (uptake of tumor antigens by antigen-presenting cells and their migration to lymph nodes), 3) Priming and activation (antigen presentation to T cells and activation of antigen-specific T cells), 4) Trafficking of T cells to tumors, 5) Infiltration of T cells into tumors, 6) Recognition of cancer cells by T cells, and 7) Killing of cancer cells.
These seven steps are shown in the figure. As the cycle progresses, tumor cells attacked and killed by T cells release new tumor antigens, leading to a resumption of the process from step 1.
If any step in this cycle is disrupted, effective induction of an anti-tumor immune response becomes difficult, allowing the cancer to escape immune surveillance. For instance, PD-1 (programmed cell death 1) expressed on activated T cells binds to PD-L1 (programmed death-ligand 1) expressed on tumor cells, transmitting an inhibitory signal to the T cell (inhibition at step 7).
ICIs work by blocking this suppression, restoring the stalled cancer-immunity cycle and reactivating the immune response against the tumor. Research has identified therapeutic strategies targeting each of these steps, with tangible results so far reported.
Currently, clinical research is entering a critical phase, employing cutting-edge technologies such as multi-omics analyses, single-cell immune profiling, genome editing techniques, immunometabolic analysis, and gut microbiota analysis. These approaches are being used in reverse translational research to identify predictive biomarkers for treatment response, guide therapy selection, develop combinatory immunotherapies, and pioneer new methods of cancer control.

In recent years, papers discussing cancer immunotherapy within the field of palliative care have begun to appear with increasing frequency [6–10]. Many of these studies are exploratory and focus on the use of ICIs in end-of-life care.
A recent US cohort study examined 242,371 patients with stage IV malignancies, including melanoma, non-small cell lung cancer, and renal cell carcinoma. The study found that physicians are increasingly administering ICIs to patients with metastatic cancer at the end of life, and that the initiation of these treatments tends to occur more frequently as the disease progresses. Notably, this trend was more prevalent in non-academic or very low-volume centers than in academic or high-volume centers [11].
Although such patterns had been observed anecdotally before, this large-scale cohort study provides scientific insights that could inform the future of immunotherapy for patients with advanced cancer [12].
While the clinical application of ICIs in palliative care holds potential, it should be approached with caution. Looking forward, even within palliative care, research into the mechanisms of immune-related adverse events (irAEs) may open the door to drug development and new therapeutic strategies. Furthermore, areas such as psycho-oncology [13], cost-effectiveness, and broader clinical ethics in the context of immunotherapy are still in their infancy.
It is essential that healthcare providers gain a deeper understanding of tumor immunology to appropriately provide cancer immunotherapy within the framework of palliative care.
Given these developments, it seems that palliative cancer care is now undergoing a significant paradigm shift.

Conclusion
Palliative care focuses not on the cancer itself, but on the host; i.e., the patient with cancer. Similarly, cancer immunotherapy targets not the tumor directly, but the patient’s immune system. This parallel structure is truly intriguing and, moreover, it reflects the core of an old yet ever-evolving concept of tumor-host interactions [14,15,16].
Furthermore, this framework offers valuable insights when considering the integration of genomic research into tumor immunology, ultimately advancing cancer care as a form of personalized medicine.