How Cancer Resists Immunotherapy: New Mechanisms Uncovered

Recent discoveries by researchers at the Salk Institute and the Centro Nacional de Investigaciones Oncológicas (CNIO) reveal distinct biological mechanisms that allow tumors to resist immunotherapy and hide from the human immune system. According to the studies, which shed light on persistent challenges in modern oncology, chronic exposure to immune-activating proteins or the action of specific tumor-derived molecules can subvert defensive bodily responses to actively promote cancer growth.

Mitochondrial Stress and Interferon Resistance

Modern oncology has long utilized immunotherapy to harness a patient’s own immune cells against cancer, yet understanding why certain tumors resist these treatments has remained a major hurdle. According to research published in the journal Science by a team at the Salk Institute in California, investigators focused on a long-standing question regarding interferons, which are proteins that normally activate and recruit immune cells like T and B cells to attack cancerous growths.

While short-term interferon exposure provides a fundamental defense against cancer, the Salk team discovered that chronic exposure alters tumor cell functioning. This prolonged cellular stress causes mitochondrial DNA, or mtDNA, to leak inside the cell, triggering a reaction sequence that ends in the massive production of a lipid known as prostaglandin E2. According to Salk Professor of Biomedical Sciences Gerald Shadel, this substance acts as a potent brake on the immune response, weakening bodily defenses and allowing the tumor to advance.

The reason why the interferons, which initially are anticancerigenic, can turn pro-cancer has been a big unknown in this field. Our study reveals a fundamental reason why interferons shift from ‘good’ to ‘bad’, as well as the way we can prevent this shift to gain therapeutic advantages in the future.

Gerald Shadel, Salk Institute

The Role of Midkine in Melanoma and Other Aggressive Tumors

Concurrently, research led by Marisol Soengas and her Melanoma Group at the Centro Nacional de Investigaciones Oncológicas (CNIO), published in Nature Cancer, examined why cutaneous melanoma and other aggressive tumors often evade detection. Cutaneous melanoma is the most aggressive and potentially mortal form of skin cancer, marked by numerous mutations that frequently go unrecognized by the immune system.

According to the CNIO findings, which involved studies in cells, mice, and over 150 patient databases, tumors utilize a protein called Midkine to reduce dendritic cells, which are responsible for recognizing tumors and regulating immune responses. Midkine reportedly reprograms these cells to favor tumor development instead of attacking it.

In this work we find that Midkine acts as a shield and accelerator at the same time; it prevents the recognition and elimination of tumor cells and, moreover, actively facilitates malignant cells to progress and spread.

Marisol Soengas, CNIO

Soengas further explained that Midkine does not merely cool the immune system down, but actively perverts it to favor tumor dissemination from an early stage across the entire organism.

Therapeutic Implications and Next Steps

Both research teams investigated how inhibiting these newly identified pathways might restore treatment efficacy. According to the CNIO, experiments in animal models demonstrated that blocking Midkine action improved the success of dendritic cell-targeted vaccines and enhanced the therapeutic action of immune checkpoint inhibitors. Furthermore, patient data analysis revealed a Midkine-associated gene signature in dendritic cells that correlates with worse prognoses in lung, breast, endometrium, adrenal gland, and mesothelioma cancers alongside melanoma.

Similarly, the Salk Institute findings point toward potential strategies to prevent the negative shift in interferon behavior. By identifying the precise molecular steps through which mitochondrial stress and lipid signaling compromise immune defenses, researchers aim to design future therapies capable of overcoming tumor resistance mechanisms.